Chothia

Brenner S E, C Chothia and T ] P Hubbard 1997. Population Statistics of Protein Structures Lessons from Structural Classifications. Current Opinion in Structural Biology 7 369-376. 

Chothia C and A M Lesk 1986. The Relation Between the Divergence of Sequence and Structure in Proteins. EMBO Journal 5 823-826. 

Chothia C, A M Lesk, A Tramontano, M Levitt, S Smith-Gill, G Air, S Sheriff, E A Padlan and D Davies 1989. Conformations of Immunoglobulin Hypervariable Regions. Nature 342 877-883. 

Murzin A G, S E Brenner, T Hubbard and C Chothia 1995. SCOP A Structural Classification of Proteins Database for the Investigation of Sequences and Structures. Journal of Molecular Biology 247 536-540. 

C Chothia, AM Lesk. The relation between the divergence of sequence and structure in proteins. EMBO J 5 823-826, 1986. 

C Chothia. One thousand families for the molecular biologist. Nature 360 543-544, 1992. 

TJP Hubbard, B Alley, SE Brenner, AGMurzm, C Chothia. SCOP A stiaictural classification of proteins database. Nucleic Acids Res 27 254-256, 1999. 

SE Brenner, C Chothia, TJ Hubbard. Assessing sequence comparison methods with reliable... 

C Chothia, AM Lesk. Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol 196 901-917, 1987. 

C Chothia, AM Lesk, M Levitt, AG Amit, RA Mariuzza, SEV Phillips, RJ Poljak. The predicted structure of immunoglobulin dl.3 and its comparison with the crystal stracture. Science 233 755-758, 1986. 

On the basis of simple considerations of connected motifs, Michael Leviff and Cyrus Chothia of the MRC Laboratory of Molecular Biology derived a taxonomy of protein structures and have classified domain structures into three main groups a domains, p domains, and a/p domains. In ct structures the core is built up exclusively from a helices (see Figure 2.9) in p structures the core comprises antiparallel p sheets and are usually two P sheets packed... 

Chothia, C. Principles that determine the structure of proteins. Annu. Rev. Biochem. S3 537-572, 1984. 

Janin, J., Chothia, C. Domains in proteins definitions, location and structural principles. Methods Enzymol. 115 420-430, 1985. 

Levitt, M., Chothia, C. Structural patterns in globular proteins. Nature 261 552-558, 1976. 

Arthur Lesk and Cyrus Chothia at the MRC Laboratory of Molecular Biology in Cambridge, UK, compared the family of globin strucfures with the aim of answering two general questions How can amino acid sequences that are very different form proteins that are very similar in their three-dimensional structure What is the mechanism by which proteins adapt to mutations in the course of their evolution ... 

To answer the first question, Lesk and Chothia examined in detail residues at structurally equivalent positions that are involved in helix-heme contacts and in packing the a helices against each other. After comparing the nine globin structures then known, the 59 positions they found that fulfilled these criteria were divided into 31 positions buried in the interior of the protein and 28 in contact with the heme group. These positions are the principal determinants of both the function and the three-dimensional structure of the globin family. 

Lesk and Chothia did find, however, that there is a striking preferential conservation of the hydrophobic character of the amino acids at the 59 buried positions, but that no such conservation occurs at positions exposed on the surface of the molecule. With a few exceptions on the surface, hydrophobic residues have replaced hydrophilic ones and vice versa. However, the case of sickle-cell hemoglobin, which is described below, shows that a charge balance must be preserved to avoid hydrophobic patches on the surface. In summary, the evolutionary divergence of these nine globins has been constrained primarily by an almost absolute conservation of the hydro-phobicity of the residues buried in the helix-to-helix and helix-to-heme contacts. 

Chothia, C., Lesk, A.M. Helix movements in proteins. Trends Biochem. Sci. 13 116-118, 1985. hothia, C., Levitt, M., Richardson, D. Helix-to-helix packing in proteins. /. Mol. Biol. 145 215-250, 1981. 

Lesk, A.M., Branden, C.-L, Chothia, C. Structural principles of a/p barrel proteins the packing of the interior of the sheet. Proteins 5 139-148, 1989. 

Chothia, C. Conformation of twisted p-pleated sheets in proteins. /. Mol. Biol. 75 295-302, 1973. 

Chothia, C., Janin, J. Orthogonal packing of p-pleated sheets in proteins. Biochemistry 21 3955-3965, 1982. 

Figure 15.13 (a) Drawing of a space-filiing model of the hypervariable regions of an Fab fragment. The superpositions of five sections are shown, cut through a model as shown in (b). It is clearly seen that all six hypervariable regions (L1-L3, H1-H3) contribute to the surface shown here. (From C. Chothia and A. Lesk, /. Mol. Biol. 196 901-917, 1987.)... 

Chothia, C., et al. Conformations of immunoglobulin hypervariable regions. Nature 343 877-883, 1989. 

Figure 17.2 An example of prediction of the conformations of three CDR regions of a monoclonal antibody (top row) compared with the unrefined x-ray structure (bottom row). LI and L2 are CDR regions of the light chain, and HI is from the heavy chain. The amino acid sequences of the loop regions were modeled by comparison with the sequences of loop regions selected from a database of known antibody structures. The three-dimensional structure of two of the loop regions, LI and L2, were in good agreement with the preliminary x-ray structure, whereas HI was not. However, during later refinement of the x-ray structure errors were found in the conformations of HI, and in the refined x-ray structure this loop was found to agree with the predicted conformations. In fact, all six loop conformations were correctly predicted in this case. (From C. Chothia et al.. Science 233 755-758, 1986.)...

The first requirement for threading is to have a database of all the known different protein folds. Eisenberg has used his own library of about 800 folds, which represents a minimally redundant set of the more than 6000 structures deposited at the Protein Data Bank. Other groups use databases available on the World Wide Web, where the folds are hierarchically ordered according to structural and functional similarities, such as SCOP, designed by Alexey Murzin and Cyrus Chothia in Cambridge, UK. 

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