The Three-Dimensional Structure of Proteins

The assembly of hair a-keratin from one a helix to a protofibril, to a microfibril, and finally, to a single hair. (Illustration copyright by Irving Geis. Reprinted by permission.) 

Coiling of a helices in a-keratins. Residues on the same side of an a helix form rows that are tilted relative to the helix axis. Packing helices together in fibers is optimized when the individual helices wrap around each other so that rows of residues pack together along the fiber axis. Helices in coiled coil (c) are oriented in parallel. 

The fi-Keratins Form Sheetlike Structures with Extended Polypeptide Chains 

Two forms of the /3-sheet structure (a) the antiparallel and (b) the parallel fi sheet. The advance per two amino acid residues is indicated for each structure. 

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Kajava, A.V., Vassart, G., Wodak, S.J. Modelling of the three-dimensional structure of proteins with the typical leucine-rich repeats. Structure 3 867-877, 1995. 

The three-dimensional structure of protein molecules can be experimentally determined by two different methods, x-ray crystallography and NMR. The interaction of x-rays with electrons in molecules arranged in a crystal is used to obtain an electron-density map of the molecule, which can be interpreted in terms of an atomic model. Recent technical advances, such as powerful computers including graphics work stations, electronic area detectors, and... 

Until quite recently, X-ray crystallography was the technique used almost exclusively to resolve the three-dimensional structure of proteins. As well as itself being technically challenging, a major limitation of X-ray crystallography is the requirement for the target protein to be in crystalline form. It has thus far proven difficult/impossible to induce the majority of proteins to crystallize. NMR is an analytical technique that can also be used to determine the three-dimensional structure of a molecule, and without the necessity for crystallization. For many years, even the most powerful NMR machines could resolve the three-dimensional structure of only relatively small proteins (less than 20-25 kDa). However, recent analytical advances now render it possible to analyse much larger proteins by this technique successfully. 

J. Greer, J. W. Erickson, J. J. Baldwin, M. D. Varney, Application of the Three Dimensional Structures of Protein Target Molecules in Structure-Based Drug Design ,./. Med. Chem. 1994, 37, 1035-1054. 

Now we can ask what is likely to happen to the three-dimensional structure of a protein if we make a conservative replacement of one amino acid for another in the primary structnre. A conservative replacement involves, for example, substitution of one nonpolar amino acid for another, or replacement of one charged amino acid for another. Intnitively, one would expect that conservative replacements would have rather little effect on three-dimensional protein structure. If an isoleucine is replaced by a valine or leucine, the structnral modification is modest. The side chains of all of these amino acids are hydrophobic and will be content to sit in the molecnlar interior. This expectation is borne out in practice. We have noted earlier that there are many different molecnles of cytochrome c in nature, all of which serve the same basic function and all of which have similar three-dimensional structnres. We have also noted the species specificity of insulins among mammalian species. Here too we find a number of conservative changes in the primary structure of the hormone. Although there are exceptions, as a general rule conservative changes in the primary structnre of proteins are consistent with maintenance of the three-dimensional structures of proteins and the associated biological functions. 

Here are the key points, (a) DNA is the stuff of genes, (b) DNA is a sequence of nucleotides, each of which carries one of four possible symbols, (c) DNA is orgaiuzed into a sequence of genes, (d) Genes determine the sequence of amino acids in proteins, (e) The sequence of amino acids determines the three-dimensional structure of proteins, which, in turn (f) determines their biological properties. These, in turn (g) determine the nature of the cell. It follows that the sequence of bases in DNA is the ultimate repository of the information required to specify the uifique biochemical personality of the cell. 

We started out this section by emphasizing the importance of getting the amino acid sequence right. After all, the sequence determines the three-dimensional structure of proteins and that, in turn, is critical for function. Through multiple mechanisms, several of which we have mentioned, translation of the genetic code is remarkably accurate. The error rate is about 1 out of 10,000. Of course, many of the errors which... 

Evidently, resolution of the three-dimensional structures of proteins will aid in the design of rational approaches for constructing drug conjugates, as demonstrated by the above-mentioned examples. Evaluation of molecular structure at this level may prove to be one of the more successful approaches used in the design of recombinant drug conjugates. 

The guanidine group is a common structural feature in Nature, primarily due to its ability to stabilize the three-dimensional structure of proteins in enzymes through binding with anionic substrates. Roush and Walts (274) prepared the... 

Hydrogen bonds and ionic, hydrophobic (Greek, water-fearing ), and van der Waals interactions are individually weak, but collectively they have a very significant influence on the three-dimensional structures of proteins, nucleic acids, polysaccharides, and membrane lipids. 

In this chapter, we explore the three-dimensional structure of proteins, emphasizing five themes. First, the three-dimensional structure of a protein is determined by its amino acid sequence. Second, the function 116... 

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