Opportunities in Biology (1989) / Chapter Skim
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3. Molecular Structure and Function
3. Molecular Structure and Function
Pages 39-76
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From page 39... ...
Included are proteins, nucleic acids, carbohydrates, lipids, and complexes of them. Many areas of biological science focus on the signals detected by these machines or the output from these machines.
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From page 40... ...
While these properties may become complex and far removed from any property inherent in single amino acids, the existence of a limited set of fundamental building blocks restricts the ultimate functional properties of proteins. Nucleic acids are potentially simpler than proteins since they are composed of only four fundamental types of building blocks, called bases, linked to each other through a chain of sugars and phosphates.
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From page 41... ...
Biological Structure Is Organized Hierarchically The structures of large biological molecules such as proteins and nucleic acids are complex. It is not practical or useful to describe these structures in words.
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From page 42... ...
Most secondary structures are helices. Some of the most frequent and best-known helices are the alpha helices found in many proteins and double helices found in virtually all nucleic acids.
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From page 43... ...
PRIMARY STRUCTURE Nucleic Acid and Protein Sequence Data Are Accumulating Rapidly The amount of available information on the primary structure of biological polymers is increasing at an astounding rate. Two decades ago we knew the nucleotide sequence of only a single small nucleic acid, the yeast alanine transfer RNA.
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From page 44... ...
Already, one can do much using the data bases to help interpret any DNA sequence plucked more or less at random from a genome. The patterns of sequence in the regions that code for the amino acid chains of proteins differ enough from the noncoding regions that the former can usually be identified.
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From page 45... ...
Clues to functional regions can emerge from amino acids that are found in places other than their usual locations. For example, in typical soluble proteins, hydrophilic residues (which have an affinity for water)
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From page 46... ...
The DNA Sequences of Entire Genomes of Some Simple Organisms Will Soon Be Known The explosion in sequence data has just begun. DNA sequencing is far easier than protein sequencing, and the tools already available for cloning and efficient sequencing of 500-base-pair blocks of DNA will ensure that the current stream of new sequence data will become a torrent.
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From page 47... ...
At present, most sequencing methods are limited to a maximum of about 500 base pairs per DNA fragment. Every significant increase in the size of the fragment that can be sequenced will improve the overall efficiency of the process.
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From page 48... ...
A second complexity of the existing data bases is that there are three independent repositories for nucleic acid sequence data: GenBank, operated by the Los Alamos National Laboratory; the EMBL data base, operated by the European Molecular Biology Laboratory in Heidelberg; and Protein Identification Resource, operated by the National Biomedical Research Foundation in Washington, D.C. The multiplicity of data bases poses severe problems for current and potential users.
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From page 49... ...
Techniques have been developed to deduce the complete structure of complex oligosaccharides, including oligosaccharides found in scarce glycoproteins, such as cell-surface molecules. Glycoproteins are proteins containing covalently attached sugars, usually short carbohydrate polymers attached to the side chains of the amino acids asparagine, serine, or threonine.
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From page 50... ...
Trying to understand the features of glycoproteins that are distinct from those of unglycosylated proteins is of current interest. Contributions of sugars to protein folding and macromolecular assembly might be fundamentally different from those of amino acids.
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From page 51... ...
THREE-DIMENSIONAL STRUCTURE The Three-Dimensional Structure of Biological Macromolecules Determines How They Function It is the three-dimensional shape of proteins and nucleic acids that endows them with their biological activities. Structural molecular biology uses x-ray diffraction, nuclear magnetic resonance, and other techniques to determine the three-dimensional arrangement of the atoms in biological molecules.
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From page 52... ...
Another structural motif has been seen in some of the proteins that recognize specific sequences of DNA and consequently regulate genes by turning them off or on. In this instance, two helical coils of protein connected by a short bend form a module that can plug into the major groove of a DNA double helix.
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From page 53... ...
For example, we know how enzymes can bind certain substrate molecules specifically, how certain amino acid side chains are positioned to act as catalysts, and how the enzyme can change its shape in response to binding the substrate or regulatory molecules. We know that sometimes these shape changes can be transmitted through the structure.
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From page 54... ...
54 ~,\ (I / 6~11 In\ ~ in, \ Jo OPPORTUNITIES INBlOLOGY _ 1~L ~ A_ 7 11 _~/ FIGURE 3-1 Cartoon of the three-dimensional structure of photoreaction center.
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From page 55... ...
Six stretches of amino acids, containing these hypervariable sequences from the heavy and light chains (See Chapter 7) of the antibody, are adjacent in space.
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From page 56... ...
It represented a neat solution to a number of chemical and biological problems, and it was easy to describe and to remember. The importance of pairing between bases on the two DNA strands and stacking of adjacent bases along each individual DNA strand is overwhelming in nucleic acid structures.
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From page 57... ...
Although no other RNA structures are yet available through diffraction procedures, the extensive use of sequence data and sequence homology has led to a large array of secondary structure predictions that will almost certainly be retained in the three-dimensional structures eventually determined. Nuclear magnetic resonance ~MR)
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From page 58... ...
First, the recent explosive growth in the power of molecular biology, as a result of gene cloning and recombinant DNA technology, suddenly provides a large amount of any given macromolecule and the ability to
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From page 59... ...
Nuclear Magnetic Resonance Is the Technique of Choice for Studying Molecular Structures in Solution Recently, NMR, a structural and analytical tool used by chemists for many years (Chapter 2) , has made rapid progress in providing information in structural biology.
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From page 60... ...
MOLECULAR ASSEMBLIES The past decade has seen major advances in our ability to study the structure of molecular assemblies. These are aggregates of individual macromolecules, most frequently complexes between proteins or proteins and nucleic acids.
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From page 61... ...
The existence of nucleosomes was first recognized by electron microscopy and from the finding of a unit of histone organization that could explain the nuclease cutting pattern of chromosomal DNA. The nucleosome was perceived and eventually proven to consist of a histone octamer about which is wrapped approximately 160 base pairs of DNA, with a single molecule of an additional histone bound on the outside.
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From page 62... ...
The amino acid sequence for a number of cell-surface receptors such as rhodopsin, the beta-adrenergic receptor, and the muscannic acetylcholine receptor have recently been determined. Analysis of the patterns of secondary structure and distribution of hydrophobic residues predicted from these sequences indicate that the 7-alpha-helical bundle is a recurring motif among cell-surface receptors.
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From page 63... ...
and the structure of the adenovirus hexon have revealed that the molecular topology of their coat proteins is essentially the same as that of the simple plant viruses. Thus all such viruses may have a common evolutionary ancestor.
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From page 64... ...
In the past five years, the determinations of the crystal structures of poliovirus, rhinovirus, and both of the surface proteins of influenza virus have allowed us to visualize those parts of the viruses recognized by the human immune system. Monoclonal antibodies and the amino acid sequences of many strains of viruses have made it possible to map the regions of each virus that are attacked by human antibodies.
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From page 65... ...
Oligomeric membrane proteins may become fairly well understood by such an approach, since the lipid bilayer imposes stringent constraints on possible transmembrane structures. The identification of residues exposed at one or the other surface of the bilayer can readily be accomplished by labeling, for example, with antibodies to specific strings of amino acids.
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From page 66... ...
Sometimes assembly occurs just by spontaneous association of individual proteins and nucleic acids, but steps in assembly are frequently accompanied by the covalent modification of key proteins and nucleic acids. Such modification can make the assembly irreversible in essence, to lock the pieces into place.
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From page 67... ...
Furthermore, one was restricted to those variants that had no lethal consequences for the organism and variants that had a significant chance of arising by natural biological mutation or evolution. The development of recombinant DNA technology has dramatically altered our study of the structure and function of proteins.
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From page 68... ...
Our ability to do this is still in its infancy; much experience will be needed before the strategies in routine use approach optimal design. However, it is already clear that the ability to alter the sequence of proteins and nucleic acids systematically has revolutionary applications for structural biology.
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From page 69... ...
The first approach to protein design is site-directed mutagenesis. Here one usually alters a single amino acid by changing one or two nucleotides in the gene at the point coding for that amino acid.
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From page 70... ...
For example, the folding of a cell-surface receptor in the lumen of the endoplasmic reticulum depends in large part on the arrangement of cysteine residues and other amino acids in the primary structure of the polypeptide. By use of site-directed mutagenesis, one can begin to vary the position and number of cysteine residues to determine their effects on the interaction of the protein with the cellular machinery of the folding process.
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From page 71... ...
These motifs are themselves complex and asymmetrical, but they are repeated in many structures. The properties of the chemically bonded atoms in the peptide chain severely constrain the possible conformations He chain can assume, and only a small number of secondary structures are possible regardless of the sequence of amino acids.
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From page 72... ...
Research in this area, a major interface between the fields of biology and chemistry, has rapidly expanded during the past five years. The basic question has always been, From chemical theory, can the threedimensional structure of a protein be derived solely from its known amino acid sequence?
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From page 73... ...
The largest hurdle one must overcome is the problem of multiple local energy minima. The potential energy function is like the surface of the earth.
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From page 74... ...
The Protein Data Bank Is a Rich Resource for Predicting Structure In the ad hoc approaches, the protein data bank is searched for patterns and statistical correlations. For example, probabilities based on the occurrence of each amino acid in various types of secondary structure differ and can, in turn, be used predictively to estimate probable regions of alpha helix, beta strand, and beta turn structures in any sequence.
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From page 75... ...
These complementary approaches to providing peptides of known sequence will play major roles in the future study of protein folding. At this time, the behavior of peptides at membrane interfaces has been studied in detail by chemical synthesis; general specifications of such interactions are starting to appear, and marked improvement in our understanding of electrostatic interactions in alpha helices seems imminent.
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From page 76... ...
The development of instruments operating at higher magnetic fields will certainly play an important role in this work. Advances in Computation Will Revolutionize the Study of Molecular Structure and Function Improved methods are needed for collecting and transmitting DNA sequences including a single, international data base.
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