Structure of Insulin

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Structure of Insulin
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Atomic orbital Nobelium Gesundheitsstörung Human subject research Ageing Functional group Onsager, Lars Controller (control theory) Metabolism Chemical structure Chemistry Biochemistry
Chain (unit) Insulin Laborzentrifuge Chemistry Molecule Enzyme Orlistat Protein Posttranslational modification Library (computing) Organische Chemie Solution Chemical reaction Erdrutsch Wine tasting descriptors Death Crown ether Stream gauge Thin film Medical history Thermoforming Calculus (medicine) Biomolecular structure Residue (chemistry) Biosynthesis Peptide Acetylcholinesterase Onsager, Lars Dörren Quartz Columbia Records Reflexionsspektrum Sample (material) Ageing Crystallographic defect Amino acid Active site Butcher Nanoparticle Process (computing) Body weight Metal Dyeing Chemistry Nobelium Song of Songs Functional group Chemical structure Alanine Separator (milk)
Chain (unit) Insulin Peptide Onsager, Lars Substitutionsreaktion Ice sheet Gold Set (abstract data type) Wursthülle Atomic number Quartz Molecule Cadmium Electron Human subject research Protein Crystallographic defect Active site Pain Periodate X-ray crystallography Chemical formula Phase (waves) Chemistry Erdrutsch Nobelium Ice Thin film Transdermales therapeutisches System Chemical compound Chemical structure Calculus (medicine)
Infrarot-Reflexions-Absorptions-Spektroskopie Chain (unit) Schwermetall Insulin Containment building Set (abstract data type) Atomic number Block (periodic table) Chemistry Alpha particle Molecule Electron Tidal race Helix Waterfall Dye Surface science Rock (geology) Solution Erdrutsch Wine tasting descriptors Electronic cigarette Systemic therapy Tiermodell Zinc Polymer Zunderbeständigkeit Calculus (medicine) Biomolecular structure Deformation (mechanics) Onsager, Lars Complication (medicine) Ice sheet Wursthülle Quartz Food Muscle relaxant Columbia Records Sulfide Origin of replication VSEPR theory Active site Tool steel Atom Phase (waves) Ice front Chemistry Nobelium Functional group Chemical structure
Residue (chemistry) Chain (unit) Insulin Peptide Onsager, Lars Complication (medicine) Set (abstract data type) Wursthülle Atomic number Molecule Diet food Cubic crystal system Potato chip Cell (biology) Active site Library (computing) Storage tank Body weight Process (computing) Main group element Fatty acid methyl ester Hydrogen bond Glättung <Oberflächenbehandlung> Chemistry Erdrutsch Electronic cigarette Wine tasting descriptors Nobelium Heck-Reaktion Feed (film) Hydrogen Zigarettenschachtel Tiermodell Functional group Chemical structure Medical history Steroid Thermoforming
Residue (chemistry) Chain (unit) Species Insulin Cell fusion Onsager, Lars Transport Gene Wursthülle Quartz Molecule Electron Tidal race Cell (biology) Ballistic trauma Posttranslational modification Active site Storage tank Cell membrane Process (computing) Area Notch signaling pathway Adamantane Chemical reaction Chemistry Erdrutsch Wine tasting descriptors Electronic cigarette Nobelium Ice Agriculture Klinische Chemie Functional group Polymer Repeated sequence (DNA) Medical history Thermoforming
it is the company's ladies and gentleman which is a very great russia to be here today and i must thank for physical limits for all of his kind words and particularly for his very useful introduction to my the subject.
of my particular a total installed in as no doubt you'll know is a hormone that is responsible for all part of the control of the metabolism of shook as and and in its absence. this disease diabetes a intervenes. it was first isolated in nineteen twenty won by a group in toronto and a cloud and ting and faced of whom based at the time was a graduate student age twenty two and.
we were able to isolate it following first of all the of much earlier evidence that the active hormone a cut in the pancreas. and that each was a protein and so they were able to take effective measures against the protein being digits to it by the enzymes that occurred in the pancreas. the next stage in the story as far as this story of mine is concerned was the crystallization instill in in nineteen twenty six able able actually was professor at johns hopkins age sixty. he said from a near retirement when protests and noise produced a small sum of ten thousand dollars and invited him with this to pasadena for a year to try to crystallize in soon in and the ten thousand. the dollar's allowed him to connect to small group of graduate students to help him and did the course of the euro they obtained the first crystals in sudan and a picture of these is on the first slide. this first picture is taken from a bulls notebook and you see he looked up mineralogical takes its and was able to describe the crystals as a trickle from dharma wrong rugby he drove class. later he was able to obtain them looking somewhat more like the form that we usually see little as wrong as. of fairly characteristic flat shape there was some difficulty for two or three years however the crystallization have ensued in squib insulin crystallised really instill in did it. and this was traced to the if occurrence in scriabin still in a small amount of sea which is necessary for the appearance of this particular modification insulin the existence of the of sync was shown vice. scott in toronto. it does also occur in the pancreas. scott found the same kinds of crystals would appear. with certain other related metals. now i. once the sink was found to have been necessary and nine to thirty four of course all the different firms making in suitland for the table in sudan crystals and a small sample of insulin crystals was given to surrogate robinson in oxford by groups when they first. made it and because he had no real intention of working on this subject himself he gave them to me i had been just come over from cambridge where i had been working with the now and had been involved with him in taking x. ray for. or to cross a feat crystalline enzyme hips and robinson full time might try to do the say take photographs and instill in so i started these a suspect history and try different methods that they had used to great insulin crystals large enough. x. ray work and i must say that one of the most exciting and nights of my life when i sold the first day ticket and spots on a photograph produced by passing aches raced through a crystal of insulin now the. takes photographs should pick next picture shows you an x. ray photograph often instill in crystal city very much better than the won the title first sold but you can see the reflections here have a definite sagnol. hatton of intensity is and a definite distance apart and from the distance a pot of this photograph combined with other as that controversy who defection a picture of ensued in one can calculate that first just the. i suffered repeating unit. this size ferries a little according to weather the crystals are weight or dry and i will put up here the mater measure and sharon you. for the size side as the wrong and forty nine.
and streams and the angle one hundred fourteen and a half degrees. first calculations the crown can make is how much but i did its allies the space i knew. good. the. thank you very much the first calculation that one can make his watch is the weight of protein in this particular volume to fight defined by two units wrong and allowing for some thirty percent of your trip. this try station the wait is just round about thirty six thousand and this seemed dramatically place to the weight of the preferred protein molecule in solution found by the first expect specimens have said. like in the out a centrifuge he gave away to thirty five thousand as the molecular way to instantly i was a little bit concerned and i discussed the problem with harrington who worked on the incident that in fact these crystals are chicken little. and that this weight should death will be divided into three equal parts twelve thousand but i published a break in a way to assess thirty five thousand possibly to fight by three and this brought an immediate to data from freud and drag in heidelberg. like saying i stayed dry doesn't really measure a molecular weight he measures of particle mess and the amount of chemical change that inactive fates instill in is so small as to suggest the molecular weight is much smaller. sarah than thirty six thousand in fact he gave an estimate of perhaps from nine to eighteen thousand which of course was nearer to the fossil twelve thousand but as the years when all on it became clear that the. and the molecules in susan was smallest still there was evidence that the particle thirty six thousand would break down in solution and gradually the evidence accumulated that the weight might even be built twelve thousand and six thousand. the that this was say was not really clear until all the next site frayed sanga found in details the structures instill in and i'm sorry this is a little bit small to read from a distance as i realized when i looked at a moment together. but essentially sanger showed that the institute in molecule consisted of two chains and the amino acids of which luckily you were shown larger picture is today i hear given that abbreviated names you see invade the entire scene alanine. and a definite order long these two chains one of twenty one result he was one of thirty visit used joined by die saw five bridges a particular points. and of course the soon as this structure was produced this chemical sequence it became possible to synthesize ensued in and three different groups set out to synthesize insulin and succeeded song in i can catch so on. in pittsburgh and a group of chinese scientists in shanghai and piquet and the knicks i'd share his. a little just what is involved in this process could i have the next one he's this is taken from one of that paper has been hess the they all synthesised separate peptides fifa and choices in the different look for trees and when they have synthesised. the a chain and the be changed and the south are at the sustain residuals is right for you it's a reduced to the a sage form and then left them in solution hopefully to get into it in the presence of an hour and some in. this shouldn't fuld not a good organic chemists a synthesis just hoping but nature would work and instill in good form i to the separate chains were. to a small degree the first products caught by this reaction had only a few percent and fifty out of thin by suitable manipulation as on the next ride crystals of insulin could be obtained.
again not perhaps it's pretty good looking crystals but you can see this fifty characteristic shape. but these are taken from the chinese paper not. say you might say we know the structure of insulin but of course it's a problem when one thinks of its these to say pretty chains how are they really disposed in three dimensions and throughout this long period from the isolation of instant in. and our first work. we really hopes to find the actual three dimensional arrangement of the institute in molecule in space. could i have been mixed like these we grew very much get to crystals than the first ones these are actually very beautiful crystals taken from a paper by a ship's crew in copenhagen. who had developed a crystallization take meeks to a fine arts because he used actual crystalline instilling fifty find a crystalline soon as the basis of a method for giving us new acting ensued into diabetes patients than they do insulins. is he also found that in these particular crystals were in general two atoms are off sink perth thirty six thousand molecular weight. how to find in detail the arrangement of the atoms in space given these crystals was in principle of course known when we started out when i started out in nineteen thirty full the next step. i'd gives later a little extract from a later and i think professor research can may recognize the writing all they the signature isn't that it's jd personnel and he was very excited because of the x. ray photographs of insulin. and he immediately suggested that one should change the sink for other eye. heavy atoms and the implication of this was that we should be able to calculate the actual electron density in the crystal if we could observe of changes in the intensity is produced by the substitution is and have and i said well for. trees. actually these at the substitutions it scott had made in toronto. but the. cadmium is rather little much fifty of them sink and the actual difference is that i could see at that time was far too small to work on also the method was and try for very much simpler compounds and. it seemed desirable to have some simplest subject from which to try out the calculation of the electron density ice and wolfowitz replacement before we tackled insulated of the knicks site just gives you i think the. dec crowd relations unfold the actual for with the calculation of the elite from thin city in the crystal at a particular point if h k l being derived from our mission once i but if if h k l. and the face angle the creepiest alpha and depend upon the positions of the atoms in the crystal and if one can vary amongst these atoms that each has its appropriate sketching number. and introduce him if you act tombs one can formally soul for the face and gold and and this of course was rocked we hope to set out to do and first substance i try this on in a very simplified fall across three. set to parts of the distribution where centrist symmetrical which simplifies the phase relations with spin is still in and i think the next lives just shows you the look of the electron density in pain is still in set up in a way to the u.. tuesday after the first time but has become the way that is used in protein crystallography today we calculate the electron density a series of figures at points. if a three dimensional space from the nation it intends to ease the ache street a fraction of fakes we have joined up a week we plotted out on an ice sheet for us to fall into dimensions and joy and contours of equal or. electron been stupid to get representation of the atomic positions and so and form a picture of actual individual atoms are on sheets of transparent a person takes all docile after material and here of course you see separate atoms. the result and on the next slide the formulas that you could write as a result of this vision of the individual asked atomic positions in space and we were lucky that any sudden is at least a little bit connected derived from a peptide kind. of skeleton. in the case of insulin as with other proteins or their the defection patch of the to see may look modest your eyes it doesn't really extend sufficiently find space for his all for individual atoms the next and pick. it just shows you the consequences of this in illustrated by a very simple molecule could i have the next one please if the space the in in pain is still in the actual a pattern extended to about point eight one else stream. the resolution this show is likely to appraise even seen it gradually reducing degrees of resolution. this being the stage at which most proteins reach and attend at least a little bit better than the case of the insulin maps we were to calculate you can see that some atoms or of us to pay out individually but in general there is less. of resolution and one has to end for the positions of the atoms from the very characteristic shapes of the electron did steep peaks that one can calculate in a protein electron did steam at our real trouble with ensued in.
that turned out to be to food and i must say i was trying to introduce hippie atoms into ensued in crystals pattern held with john kendra next produced at cambridge even he moved to a beating and mark davies. and we got. we had no single chemical point at which we could attach a hit the atom as in the case of humor day been but we thought perhaps therefore we should follow the line far and i can do and try to get just. haiti atoms to parse into the crystals i also means and actually it was carlisle working with the now through first produced the idea could take them into the crystal by just soaking you him into solution so we tried to get a great many experiments. and we five get ready difficult to find with a heavy atoms when he and here i have to stop to take go back a stage with my full money the first thing one can calculate is not of course the electron density one. i can only begin to calculate the paterson taking the f. squared values and obtaining a derived function of the electron density will the next side i think should show you could have next one he's a pass and. map for insulin and this is just a beautiful three dimensional had to some five shun and actually it's quite interesting we started by thinking we could know nothing a tool for a moment but you can see something from it this is just part of the function and in dispatched and you do see infect thirty rock. three planes of symmetry which don't extend the whole race through the crystal but it very complicated past the implication of those planes of symmetry is shown in the next slide. it is is that he instantly in in the unit sell we have in this thirty six thousand mess six molecules and the six molecules of course three are arranged around the three fed ex is standing in front of it to three. but the other two ababa triplett is arranged so that there's a two fold axis relation approximately between them and so over here. the pattison function derived from this show is plains of symmetry pattison function is caught by imagining you stand of each after mean to put the chatham in turn that the origin and pull her to function arrived at six derived from eat that much. little complicated. at this point two things became obvious first was that if this if the only to zinc atoms in the crystal as street crew had found they must lie on the three failed exits and that was one great help. and secondly that we would expect that as a heavy atoms introduced into the crystal should have this katich trusted patten and so if we did a difference math taking measuring the intense does have a crystal and the heavy atom we should see this sort of pet. and in the different spent the first point was quite all right to seek atoms on the three food x. is the second turned out to be a small have they seldom if ever showed anything like the courage symmetry for reasons that are now obvious that makes side i think just. phase one of the difference paterson's of the heavy atoms a very complicated looking won but the little keeps could you shocked initial distilled yet the origin to imply that they hit the atom in this crystal has gone india to three fed ex is now. the hippie atom in this particular case was a very interesting one. it has got i taking sink in sudan crystals leaving them if a night in eg t a solution to this remove the synchro the crystals and lift us with crystal standing looking rival sorry for themselves but still says and containing. we are still giving x. ray to fractured its and if we didn't live amid made a fun night because eight when into positions on a pied piper the sink and also into physicians represented by this mad and to some others on the outside of the molecule. and i will not cut a very long story short of how different hit the atom and positions were found and take you essentially to the on some so on the next slight i have for us to fool the physicians found fall for. front five different paper yet some containing crystals plotted along with three failed axis over. unit of for human which covers how to instill in mild hixon. and and you can see its shop and a little that they may face a lot of them come round to three failed axis the patten doesn't have to fold symmetry seem to be too general sorts of positions one the other three fed ex's and one out. on the edge of our for molecules week later handed. and our difficulty was that the soldiering out to this very complicated a pattern of heavy atoms before we could calculate the face or nations and three dimensional structure been sued but now the pasta the actual in a. confidence to map said the actual calculation came through the middle of july last year on and we cut it out and threw it out and i would show you the original map because we have drawn it all much better since then. but the next sides are taken from a little model for the night for the ira penny soon model and but representing the three is the electron dance to as we calculated it over the insulin hixon and because it's a. watch molecules and this hexham earth this is thirty engstrom steep and forty six and systems across the actual little blocks are broken up into and five or six and i would just won the sites through said you can imagine yourself.
looking at the molecule from top to bottom and thinking what you could see the next this is the top of it a bit empty could be shot with a little bit could be shop under the the the are desperate or is this is the top of it looking a little bit empty. or rather complicated set of changes are these a half a dozen sheets predicted to get the now under mixed could be passed on to the next one now you see where thickening app tremendously in one particular region. a lot of peaks coming together and interests in this part this the peak beginning of the sink atom and these three peaks of three peaks is or buffett and the next ride it's becoming a bit more understandable sharpen up a bit more he has the the sink. here and now these three peaks of three peaks that underneath it. and they seem to run into a very different shade structure he a with peaks coming all fitted certain intervals and at this point we began to be looking at sang a sequence and seeing what we might thinking rocking might seeing because we knew is that this chemical evidence that the. his team groups of insulin interacted with the sink and say we looked at what would be a the to his to the race it use and in one case he studied ten if we take this is his to be in and count on one side of it. it goes to a series coming back towards the a sink and on the other side goes out to have you seen and here is a peak with the kind of and relax and that could be a new cd and from this point we started chasing through the chain now just choose the next. to that if we could go on to the next one that this is possibly because so that particular point and hot here we come to a highly empty beaches the middle of the crystal with chains coming into wards the central cavity and this is the central cavity into which. so many of his the atoms when to into somewhat random way in our substitution and the next round pissing down below the central point that we begin to see another a similar change his to been on the other side coming in the you see on. the other side and the c.r.u. on the other side and they don't trust absolutely the same but that the since sensibly the same sort of object and then dimebon their debt to the next slide to sync with the other three little groups about it and the beginning so. the top of all bottom of the molecule the other site so now you have passed through it all and in about a week we have traced very rapidly where we thought everything was in the insulin molecule. but then we've taken a year are going through every single criteria actually it isn't it well as any facts are eighteen months isn't it. and going through everything much more carefully comparing the electron dance team that directly with a much more accurately built model of a model of two centimeters to the extreme. which we could project directly into a map of the electron against it the same scale by a mirror device and produced in oxford by our purpose of fred richards from yale when he was visiting that fall which we call in arcs. offered freights fall in which doesn't mean a fillet in in a flourish states but because of quality is a special kind of little or had matter how does a delight to see for all of us who were at cricket and so on the next side i think i have a. little bit showing you how clearly street you can in fact seats the appearance of the race it used to the shape of the peaks as they have come out in this three dimensional electron dense to met and. at the present moment we have passed away over the molecules and recorded positions in three dimensions to a first approximation for every atom in the molecule us so the next few slides if i might happen. just show you the look of each chain in turn. all the time predicted in the same direction longer three failed axes and now this is one of the be chains of sag as molecule. and it starts up with that in the one which is a federal alanine group and it ran as an extended formed as far as this feet ten his to dean which comes into the sink and they turned us through and three turns a very good as the helix and and then it runs. write down and write up in another extended shade its way to fix afterwards you look at the modern because then you can see what's happened you come alone the dec you go into the south the helix straight down and denise and then you come up in the long chain right track here. to the topic in and now the a chain on the next side just sort of nestles into the the chain it just forms a little closed loop. see starting here and getting dollars that just lie on the face of the chain and the dye sulfide links that link the two chains together on a link to see a while at this end to the alpha he explained as and the other one of the other day and to the other end of the alpha here. six said that the alpha he makes he little part of the be changed from some kind of rigid skeleton on which the ha nice and now at the other side i shared with the other two molecules this is the second molecule in the asymmetric unit again. under the be change starting out a long stretch of of extended shade a the alpha helix coming down here and then we're seeing this law will end of the chain are coming up on aid and on the next slide. the second a chain again and forming this small old very compact to do with in sea and over the surface of the chain and now you put these two together and in the lakeside you have the same project. question of the insular and diana with the two molecules together and i think you can begin to see that where is this lie is an approximate to float exes it isn't by any means an exact tooth and x's that the site difference.
is in the relative positions of the groups on either side of it. now the actual shape of this time and i'm sorry but i haven't got it here in london and prison spur for you is and a rather a long gated overrule the next side shows you a few on the side along the sides. off the dime or as seen in this. more accurate model three had in oxford which the boys wait let's move away from oxford even to be shared at the royal society if the piste because they regard it as such a delicate objects that hester preserved in the exact form in which they have little to it. but anyway here is at one one week you will and the second molecule packed together with the to sink atoms along the three failed axis each of which has directed at it his to dinner a city and if this is. if you'd from the earth. direction of the sink atoms and the next side shows you the view from the direction of from from the outside the molecule and now if you could shoot craps we might be its have a little demeaning and the rest of its at this stage this shows you that. and these two molecules are fitted together in a very intricate way it's better the main groups that packed together on on paris it use but there is a very long region here with hydrogen bonds formed between. the extended ends off the beach aid this is the extended end for one more this was going up in this direction and this is the extended and thousand coming down the straight should and hydrogen bonds formed across here you can see them in red said that this is part of the n.. to pattern lp to cheat and it's between the two a insulin molecules now the next slide and share is this just drawn out said you can see the weight it goes with the hydrogen bombs forming a on either side of the two thirty. texas in this generally and to have an lp to cheat for that now if we look down the two failed to a on to the two photos exes that's to say the way we think looking most of the time we can see that while these groups have quite nicely related to the individual residues. i'm not could we have the next side and the and. this is looking onto it and not a result use the project are runs like yard a fan or alan means and really these finland a means to be related i did too filled x. is one should turn away in one direction and the other when the opposite direction but in fact the second one turns a. cross it. to it to in order to pack side by side nicely us cannot groups and like to do this regarding his two friends symmetry and up here again the fame the group's don't seem to have the same. and orientation and again it looks as if they just turned to fit nicely into one another for this or are nonpareil interaction that point and at the end we have to be thirteen and glutamate ions going into the centre and they are the ones which attract these heavy. the atoms into the central pool of the insulin one q now the next slide i think share receive just to give you an impression to get called from the diver to the heck summer. is this the a projection of all of the atoms in the unit cielo of insulin and safe are placed by us that's to say the atoms belong to the molecule and you can see that these six instrument molecules have formed a very good says. this federal aid or object and the steroids or objects tech together in the next lived in a way to to justice is scary quite good trace packing of its it's actually cubic police into case for packing but you can see the way these. medical objects the incident hixon as sit together in the crystal structure so now or we should think in all the tale of bikes the complications of this molecule and watch it is doing in iowa in nature and this is to. we'll have a very great history we have this very complicated arrangement of chains within the molecule which yet ends out to sea producing a very remarkable smoothly steroids will object and this smoothly. as for idol object it seems does exist in the living body of course the places i which the body makes institute in our set in a quite different from those used in the taste you and to stocked with evidence has been. in a crowded he recently set in sudan is not synthesised and the bloodiest to separate chains. a single chain prayer instilled in us discovered by stein a in chicago i had the next i'd this is the way for it. the body synthesizes instill in as a single chain governed by the usual process is and fla no diet genetic prices is the need to a single shade and then at a point in its. in the pancreas. when it is transferred from the site which is synthesized to the storage sales the islet cells of lanka hands. the creative approaches to get inside chip self and this very long peptide fragment that connects the two chains and there it is a sort of curious point about this if one looks the at the molecule because at one might think this. connecting peptide had to bring certain parts of the molecule get together actually these parts of any case to get for the the the actual beginning of the a chain of the end to the chadian spaced the beginning of the a chain is just down about here. and the end of the chain here in the body to see only about two residuals apart said had been fears that be heard of this long peptide isn't necessary and only for all are bringing feed and chain structure that for him.
encouraging particular folding of the chain that we have in the insulin molecule in there are very interesting points about princeling when it does seems that if you break the thyself five bridges in princeton in the chain's for and again much better than insulin.
and perhaps the long chain provides some kind of for a template to on which the molecule lives which encourages the great full of the of the incident like you'll already provide some kind of protection for the molecule in its transport. to the storage site now the next slide shows a picture off the actual storage in sudan in the islet cells and not have this is taken actually from right islet cells and by dr howells in sussex and. i think you can see that the little in soon granules look sensibly is if they with crist live they looked like little crystals and indeed in some animals you can see quite a notch crystals but here they have the full very much the same form as the crystals that we have been. and working on if he slices of these little crystals fusion hire car in the electron microscope and in the next slide you can see a feat distance across them in some few was you get a view of lions of off the. as of right accused and if you look at the size of the molecule in the distance across of these lines the distances from about fifty extremes which is sensibly the other side of the round he drove unit the distance apart of repeating. hicks of us so it seems almost certain that in the actual as insulin and yeah i'm it sells in sudan is stored in d.c. containing expense but now the problem is what is it doing and here i have to stray this apron really to the orgy. once the next i'd just cherie's some of the different kinds of biological process is in which ensued and has been implicated by a large number of experiments and of these of course the original lions have seemed most. the important where wines involving could have a visible flu case and particularly possibly the transport a group case through membranes we invite and observations on this molecule at this point but i might just add. one more piece of evidence to it we at forty to be interesting to look into the actual and. mission at which ice the insulin molecule appeared to be able to change in different species without reducing its effect that's to say to me that the species. differences in in soon in following the same kinds of ideas that shock to sing was talking about an area so in the next side i have not all that quite a number of the if you could be shop and a little bit more. it sets better you can see that many of the race jews are allowed to change and when you look at the ones that they would change their generally lower yet the sistine hasn't changed the new scene has to change eight nineteen tires seen a twenty one spot. seen spatter gene hasn't changed but is tremendous lot of changes you could serve in the next side we have just got a little map showing where now the invariable residues aisle in the molecule us we see this is a single. molecule and devotees archie a ones that seem to be involved in and putting the molecules into its actual confirmation you see. the sistine races use of course but also it to us reduce events that are involved in as you might say the heart of the molecule. and then this leaves us with just one or two on the outside and a nineteen tara scene is one particular and eight and dispatcher gene which are also in fairy and say farm lost sight just chased gifts you a picture of. on the molecule. and it's just as this molecule and sweet you look at it here but drawn from the actual the electron danced the map the actual positions taken out of the electron dense to map and it's ready to give you an impression of fun. after approaching reagents would be seeing you see this face full of all detail and one asked us oneself what parts of it are important for the actual biological reaction is it at a particular region on this face or is it the whole. rule organize a shunned and is it for monem a single in sudan molecule a sanger believes or to die in a stable you feel york or the hc summer as we sometimes believe our selves when we see at the very beautifully organized subject the tea is. with pockets in it that might carry things about to hit. and not and this is still to be found out. before i leave this subject i should say two things rather crystalline modifications have ensued in very interesting ones which are being worked on at the moment he also run dick for which contains no to sink in colombia by dr barbara know that the model. clinic for which contains take some assist its asymmetric unit by michael rosman in third you and i shot at the end i should also say that in this particular research. the sum total of the co-workers was much the part played by the care workers the sum total was much greater the part played by for profit. caught take feel words from you. is it should get and at that i should mention particularly those who carried through the last stages of the analysis had rather long history market adam and tom bundle from oxford. i don't seen from new zealand elena dogs being from australia they may to manage in oxford and a giant from bangalore all and i must say we paki chase him because his name made late victory. she proved.