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thornton-structurefunction-NSB2000 - 2000 Nature America...

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progress The essence of structural genomics is to start from the gene sequence, produce the protein and determine its three-dimen- sional structure. The challenge, once the structure is determined, is to extract use- ful biological information about the bio- chemical and biological role of the protein in the organism. This is a com- plete reversal of the classical structural biology paradigm, where a protein structure is determined to understand how it performs its known biological function at the molecular level. Here we summarize some current approaches to this problem, including the challenges that still remain and briefly address the implications for drug design and target discovery. A more nature structural biology • structural genomics supplement • november 2000 991 detailed review with a comprehensive reference list can be found in ref. 1. Structural data It is first useful to summarize what information can and cannot be derived from structural data (Fig. 1). The structure reveals the overall organization of the protein chain in three dimensions. From this we can identify the residues that are buried in the core or exposed to solvent on the protein surface, the shape and mol- ecular composition of the surface, and the relative juxtaposition of individual groups. It also reveals the quaternary structure of the protein in the crystal environment or in solution at high con- centration. Protein–ligand complexes are perhaps the most use- ful for functional information, since they reveal the nature of the From structure to function: Approaches and limitations Janet M. Thornton 1,2 , Annabel E. Todd 1 , Duncan Milburn 1 , Neera Borkakoti 3 and Christine A. Orengo 1 This review presents a summary of current approaches to extract functional information from structural data on proteins and their complexes. While structural homologs may reveal possible biochemical functions (which may be hidden at the sequence level), elucidating the exact biological role of a protein in vivo will only be possible by including other results, such as data on expression and localization. 1 Biochemistry & Molecular Biology Dept., University College, Gower Street, London WC1 6BT, UK. 2 Crystallography Dept., Birkbeck College, Malet Street, London WC1 7HX, UK. 3 Roche Discovery Welwyn, Broadwater Rd, Welwyn Garden City, Hertfordshire, AL7 3AY, UK. Correspondence should be addressed to J.M.T. email: [email protected] Fig. 1 From structure to function: a summary of information that can be derived from three-dimen- sional structure, relating to biological function. © 2000 Nature America Inc. • http://structbio.nature.com © 2000 Nature America Inc. • http://structbio.nature.com
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about the relationship between protein function and structure? The same fold is often seen in apparently different homologous families with different functions. (Fig. 2 a ). Martin et al.
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