The Structures Of Life - NIGMS Home
The Structures of LifeU.S. DEPARTMENT OFHEALTH AND HUMAN SERVICESNational Institutes of HealthNational Institute of General Medical SciencesNIH Publication No. 07-2778Reprinted July 2007http://www.nigms.nih.gov
ContentsPR E FACE : W H Y S TR U C T U R E ?ivCH A PTE R 1: PR O TE I N S AR E T H E B O DY’ SW O R KE R M O L E C U L ESProteins Are Made From Small Building BlocksProteins in All Shapes and SizesComputer Graphics Advance ResearchSmall Errors in Proteins Can Cause DiseaseParts of Some Proteins Fold Into CorkscrewsMountain Climbing and Computational Modeling2344678The Problem of Protein Folding8Provocative Proteins9Structural Genomics: From Gene to Structure, and Perhaps FunctionThe Genetic Code1012CH A PTE R 2: X-RAY C RYS TALLO G R AP H Y:A R T M A R R I E S S C I EN C EViral VoyagesCrystal CookeryCalling All CrystalsStudent Snapshot: Science Brought One Student From theCoast of Venezuela to the Heart of Texas1415161718Why X-Rays?20Synchrotron Radiation—One of the Brightest Lights on Earth21Peering Into Protein FactoriesScientists Get MAD at the Synchrotron2324
C H A PTE R 3: TH E W O R LD O F N MR :M AG NE TS , R A DI O WAVE S , AN D D E T E C T I VE W O R KA Slam Dunk for EnzymesNMR Spectroscopists Use Tailor-Made ProteinsNMR Magic Is in the MagnetsThe Many Dimensions of NMR2627282930NMR Tunes in on Radio Waves31Spectroscopists Get NOESY for Structures32The Wiggling World of Proteins32Untangling Protein FoldingStudent Snapshot: The Sweetest Puzzle3334C H A PTE R 4: S TR U C TU R E -B AS E D D R U G D E S I G N :FR O M TH E CO M PU TE R T O T H E C LI N I CThe Life of an AIDS VirusRevealing the TargetStructure-Based Drug Design: Blocking the LockA Hope for the Future3636384244How HIV Resistance Arises44Homing in on ResistanceStudent Snapshot: The Fascination of Infection4546Gripping Arthritis PainC H A PTE R 5: BE YO ND D R UG D E S I G N4852Muscle Contraction52Transcription and Translation53Photosynthesis54Signal Transduction54GLO S SARY56
P R E FA C EWhy Structure?magine that you are a scientist probing the secretsIprotein offers clues about the role it plays in theof living systems not with a scalpel or microscope,body. It may also hold the key to developing newbut much deeper —at the level of single molecules,medicines, materials, or diagnostic procedures.the building blocks of life. You’ll focus on theIn Chapter 1, you’ll learn more about thesedetailed, three-dimensional structure of biological“structures of life” and their role in the structuremolecules. You’ll create intricate models of theseand function of all living things. In Chaptersmolecules using sophisticated computer graphics.2 and 3, you’ll learn about the tools —X-rayYou may be the firstperson to see the shapeof a molecule involvedin health or disease.You are part of theIn addition to teaching about our bodies, these“structures of life” may hold the key to developingnew medicines, materials, and diagnostic procedures.growing field ofstructural biology.The molecules whose shapes most tantalizecrystallography and nuclear magnetic resonancestructural biologists are proteins, because thesespectroscopy —that structural biologists usemolecules do much of the work in the body.to study the detailed shapes of proteins and otherLike many everyday objects, proteins are shapedbiological molecules.to get their job done. The shape or structure of a. Proteins, like many everyday objects,are shaped to get their job done.The long neck of a screwdriver allowsyou to tighten screws in holes or pryopen lids. The depressions in an eggcarton are designed to cradle eggsso they won’t break. A funnel’s widebrim and narrow neck enable thetransfer of liquids into a containerwith a small opening. The shapeof a protein— although much morecomplicated than the shape ofa common object — teaches usabout that protein’s role in the body.
Preface I vChapter 4 will explain how the shape of proteinscan be used to help design new medications — inthis case, drugs to treat AIDS and arthritis. Andfinally, Chapter 5 will provide more examples ofhow structural biology teaches us about all lifeprocesses, including those of humans.Much of the research described in this bookletis supported by U.S. tax dollars, specifically thoseawarded by the National Institute of GeneralMedical Sciences (NIGMS) toscientists at universities across thenation. NIGMS is one of the world’stop supporters of structural biology.NIGMS is also unique amongthe components of the NationalInstitutes of Health (NIH) in that itsmain goal is to support basic biomedicalresearch that at first may not be linked to aspecific disease or body part. These studiesincrease our understanding of life’s most funda mental processes — what goes on at the molecularand cellular level — and the diseases that resultwhen these processes malfunction.Advances in such basic research often lead tomany practical applications, including new scientifictools and techniques, and fresh approaches todiagnosing, treating, and preventing disease.Alisa Zapp MachalekScience Writer and Editor, NIGMSJuly 2007. Structural biology requires thecooperation of many differentscientists, including biochemists,molecular biologists, X-raycrystallographers, and NMRspectroscopists. Although theseresearchers use different techniquesand may focus on different molecules,they are united by their desireto better understand biology bystudying the detailed structureof biological molecules.
CHAPTER 1Proteins Are the Body’s Worker MoleculesYou’ve probably heard that proteins arecirculate in your blood, seep from your tissues,important nutrients that help you buildand grow in long strands out of your head.muscles. But they are much more than that.Proteins are also the key components of biologicalProteins are worker molecules that are necessarymaterials ranging from silk fibers to elk antlers.for virtually every activity in your body. TheyProteins are worker molecules that are necessaryfor virtually every activity in your body.A protein called alpha-keratinforms your hair and fingernails,and also is the major componentof feathers, wool, claws, scales,horns, and hooves.Muscle proteins called actinand myosin enable all muscularmovement—from blinking tobreathing to rollerblading.Receptor proteins stud the out side of your cells and transmitsignals to partner proteins onthe inside of the cells.Antibodies are proteinsthat help defend your bodyagainst foreign invaders, suchas bacteria and viruses.The hemoglobin protein carriesoxygen in your blood to everypart of your body.Ion channel proteins control brainsignaling by allowing small mole cules into and out of nerve cells.Enzymes in your saliva, stomach,and small intestine are proteinsthat help you digest food.Huge clusters of proteins formmolecular machines that do yourcells’ heavy work, such as copy ing genes during cell division andmaking new proteins. Proteins have many different functions in our bodies. By studying the structuresof proteins, we are better able to understand how they function normally and howsome proteins with abnormal shapes can cause disease.
Proteins Are the Body’s Worker Molecules I 3Proteins Are Made From SmallBuilding BlocksProteins are like long necklaces with differentlyshaped beads. Each “bead” is a small moleculecalled an amino acid. There are 20 standard aminoacids, each with its own shape, size, and properties.Proteins typically contain from 50 to 2,000amino acids hooked end-to-end in many combi nations. Each protein has its own sequence ofamino acids.These amino acid chains do not remain straightand orderly. They twist and buckle, folding in uponthemselves, the knobs of some amino acids nestlinginto grooves in others.This process is complete almost immediatelyafter proteins are made. Most proteins fold inless than a second, although the largest and mostcomplex proteins may require several seconds tofold. Most proteins need help from other proteins,called “chaperones,” to fold efficiently.Proteins are made of aminoacids hooked end-to-end likebeads on a necklace.To become active, proteinsmust twist and fold into theirfinal, or “native,” conformation.This final shape enables proteinsto accomplish their function inyour body.
4 I The Structures of LifeProteins in All Shapes and SizesBecause proteins have diverse roles in the body, they come inmany shapes and sizes. Studies of these shapes teach us howthe proteins function in our bodies and help us understanddiseases caused by abnormal proteins.To learn more about the proteins shown here, and manyothers, check out the Molecule of the Month section of theRCSB Protein Data Bank (http://www.pdb.org).Molecule of the Month images by David S. Goodsell, The Scripps Research InstituteAA ntibodies are immune system proteins that ridthe body of foreign material, including bacteria andviruses. The two arms of the Y-shaped antibodybind to a foreign molecule. The stem of the antibodysends signals to recruit other members of theimmune system. Some proteins latch onto and regulate the activityof our genetic material, DNA. Some of theseproteins are donut shaped, enabling them to forma complete ring around the DNA. Shown here isDNA polymerase III, which cinches around DNAand moves along the strands as it copies thegenetic material.
Proteins Are the Body’s Worker Molecules I 5Computer Graphics Advance ResearchEnzymes, which are proteinsthat facilitate chemical reactions,often contain a groove or pocketto hold the molecule they actupon. Shown here (clockwisefrom top) are luciferase, whichcreates the yellowish light offireflies; amylase, which helpsus digest starch; and reversetranscriptase, which enablesHIV and related viruses toenslave infected cells.Decades ago, scientists who wanted to studythree-dimensional molecular structures spent days,weeks, or longer building models out of rods, balls,and wire scaffolding.Today, they use computer graphics. Within sec onds, scientists can display a molecule in severaldifferent ways (like the three representations of asingle protein shown here), manipulate it on thecomputer screen, simulate how it might interactwith other molecules, and study how defects inits structure could cause disease.To try one of these computer graphics programs,go to http://www.proteinexplorer.org orhttp://www.pdb.org. A ribbon diagram highlightsorganized regions of theprotein (red and light blue). A space-filling molecular model. Collagen in our cartilageand tendons gains its strengthfrom its three-stranded, ropelike structure.attempts to show atoms asspheres whose sizes correlatewith the amount of space theatoms occupy. The sameatoms are colored red andlight blue in this model andin the ribbon diagram. A surface rendering of the sameprotein shows its overall shapeand surface properties. The redand blue coloration indicates theelectrical charge of atoms onthe protein’s surface.
6 I The Structures of LifeSmall Errors in Proteins Can Cause DiseaseSometimes, an error in just one amino acid canThe disease affects about 1 in every 500 Africancause disease. Sickle cell disease, which mostAmericans, and 1 in 12 carry the trait and can passoften affects those of African descent, is causedit on to their children, but do not have the diseaseby a single error in the gene for hemoglobin,themselves.the oxygen-carrying protein in red blood cells.This error, or mutation, results in an incorrectAnother disease caused by a defect in oneamino acid is cystic fibrosis. This disease is mostamino acid at one position in the molecule.common in those of northern European descent,Hemoglobin molecules with this incorrect aminoaffecting about 1 in 2,500 Caucasians in the Unitedacid stick together and distort the normallyStates. Another 1 in 25 or 30 are carriers.smooth, lozenge-shaped red blood cells intojagged sickle shapes.The disease is caused when a protein calledCFTR is incorrectly folded. This misfolding isusually caused by the deletion of a single aminoacid in CFTR. The function of CFTR, which standsfor cystic fibrosis transmembrane conductanceNormal Red Blood Cellsregulator, is to allow chloride ions (a componentof table salt) to pass through the outer membranesSickled Red Blood Cellsof cells.When this function is disrupted in cystic fibrosis,The most common symptom of the diseaseglands that produce sweat and mucus are mostis unpredictable pain in any body organ or joint,affected. A thick, sticky mucus builds up in thecaused when the distorted blood cells jam together,lungs and digestive organs, causing malnutrition,unable to pass through small blood vessels. Thesepoor growth, frequent respiratory infections,blockages prevent oxygen-carrying blood fromand difficulties breathing. Those with the disordergetting to organs and tissues. The frequency,usually die from lung disease around the age of 35.duration, and severity of this pain vary greatlybetween individuals.
Proteins Are the Body’s Worker Molecules I 7Parts of Some Proteins Fold IntoCorkscrewsWhen proteins fold, they don’t randomly wadup into twisted masses. Often, short sections ofproteins form recognizable shapes. Where aprotein chain curves into a corkscrew, thatsection is called an alpha helix. Where itThese organized sections of a protein packtogether with each other—or with other, lessorganized sections—to form the final, foldedprotein. Some proteins contain mostly alphahelices (red in the ribbon diagrams below).Others contain mostly beta sheets (light blue),or a mix of alpha helices and beta sheets.forms a flattened strip, it is a beta sheet.Images courtesy of RCSB Protein Data Bank(http://www.pdb.org)
8 I The Structures of LifeThe Problem of Protein FoldingA given sequence of amino acids almost alwaysfolds into a characteristic, three-dimensionalstructure. So scientists reason that the instructionsfor folding a protein must be encoded within thissequence. Researchers can easily determine a protein’samino acid sequence. But for more than 50 yearsthey’ve tried —and failed—to crack the code thatgoverns folding.Scientists call this the “protein folding problem,”and it remains one of the great challenges instructural biology. Although researchers haveMountain Climbing andComputational ModelingMany scientists use computers to try tosolve the protein folding problem. Oneexample is David Baker, a mountainclimber and computational biologistteased out some general rules and, in some cases,can make rough guesses of a protein’s shape, theycannot accurately and reliably predict the positionof every atom in the molecule based only on theamino acid sequence.The medical incentives for cracking the foldingcode are great. Diseases including Alzheimer’s,cystic fibrosis, and “mad cow” disease are thoughtat the University of Washington. Heto result from misfolded proteins. Many scientistsdesigns software to predict proteinbelieve that if we could decipher the structures ofstructures—and harnesses unusedproteins from their sequences, we could betterunderstand how the proteins function and mal computer power from college dormfunction. Then we could use that knowledge torooms to do so. Read about it atimprove the treatment of these gs/sept05/business.html.
Proteins Are the Body’s Worker Molecules I 9Provocative Proteins Each one of us has several hundred thousanddifferent proteins in our body. Sometimes ships in the northwestPacific Ocean leave a trailof eerie green light. The light Spider webs and silk fibers are made of thestrong, pliable protein fibroin. Spideris produced by a protein injellyfish when the creaturessilk is stronger than a steel rodare jostled by ships. Because theof the same diameter, yet it istrail traces the path of ships atmuch more elastic, so scientistsnight, this green fluorescenthope to use it for products as diverse asprotein has interested the Navybulletproof vests and artificial joints. Thefor many years. Many cell biologists also use itdifficult part is harvesting the silk, becauseto fluorescently mark the cellular componentsspiders are much less cooperative than silkworms! The light of fireflies (also called lightning bugs)they are studying. If a recipe calls for rhino horn, ibis feathers,is made possible by aand porcupine quills, try substituting yourprotein called luciferase.own hair or fingernails. It’s all the sameAlthough most predatorsstuff — alpha-keratin,stay away from the bitter-a tough, water-resistanttasting insects, some frogsprotein that is also theeat so many fireflies that they glow!main component of wool,scales, hooves, tortoise shells, The deadly venoms of cobras, scorpions, andpuffer fish contain small proteins that act asnerve toxins. Some sea snails stun their prey(and occasionally, unlucky humans) with up to50 such toxins. One of these toxins has beendeveloped into a drug calledPrialt , which is used to treatsevere pain that is unrespon sive even to morphine.and the outer layer of your skin.
10 I The Structures of LifeStructural Genomics: From Gene toStructure, and Perhaps FunctionThe potential value of cracking the protein foldingcode skyrocketed after the launch, in the 1990s, ofgenome sequencing projects. These ongoing projectsgive scientists ready access to the complete geneticsequence of hundreds of organisms — includinghumans.From these genetic sequences, scientists caneasily obtain the corresponding amino acidsequences using the “genetic code” (see page 12).The availability of complete genome sequences(and amino acid sequences) has opened up newavenues of research, such as studying the structureof all proteins from a single organism or comparing,across many different species, proteins that play aspecific biological role.The ultimate dream of structural biologistsaround the globe is to determine directly fromgenetic sequences not only the three-dimensionalstructure, but also some aspects of the function ofall proteins.They are partially there: They have identifiedamino acid sequences that code for certain structuralfeatures, such as a cylinder woven from beta sheets.Researchers have also cataloged structuralfeatures that play specific biological roles. Forexample, a characteristic cluster of alpha helicesstrongly suggests that the protein binds to DNA.But that is a long way from accuratelydetermining a protein’s structure based onlyon its genetic or amino acid sequence. Scientistsrecognized that achieving this long-term goalwould require a focused, collaborative effort. Sowas born a new field called structural genomics.In 2000, NIGMS launched a project in struc tural genomics called the Protein StructureInitiative or PSI (http://www.nigms.nih.gov/Initiatives/PSI). This multimillion-dollar projectAs part of the ProteinStructure Initiative,research teams acrossthe nation have deter mined thousands ofmolecular structures,including this structureof a protein from theorganism that causestuberculosis.involves hundreds of scientists across the nation.The PSI scientists are taking a calculatedshortcut. Their strategy relies on two facts.First, proteins can be grouped into familiesbased on their amino acid sequence. Members ofthe same protein family often have similar struc tural features, just as members of a human familyCourtesy of the TB StructuralGenomics Consortiummight all have long legs or high cheek bones.
Proteins Are the Body’s Worker Molecules I 11Second, sophisticated computer programspossible to solve structures faster than ever before.can use previously solved structures as guides toBesides benefiting the PSI team, these technologiespredict other protein structures.have accelerated research in other fields.The PSI team expects that, if they solve a fewPSI scientists (and structural biologists world thousand carefully selected protein structures, theywide) send their findings to the Protein Data Bankcan use computer modeling to predict the struc at http://www.pdb.org. There, the information istures of hundreds of thousands of related proteins.freely available to advance research by
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