Fold structural genomics

Invent computer methods to predict the three-dimensional folded structure of a protein—and the pathway by which folding occurs—from its amino acid sequence, so information from the human genome can be translated into the encoded protein structures. 

The term "structural genomics" is used to describe how the primary sequence of amino acids in a protein relates to the function of that protein. Currently, the core of structural genomics is protein structure determination, primarily by X-ray crystallography, and the design of computer programs to predict protein fold structures for new proteins based on their amino acid sequences and structural principles derived from those proteins whose 3-dimensional structures have been determined. Plant natural product pathways are a unique source of information for the structural biologist in view of the almost endless catalytic diversity encountered in the various pathway enzymes, but based on a finite number of reaction types. Plants are combinatorial chemists par excellence, and understanding the principles that relate enzyme structure to function will open up unlimited possibilities for the... 

Wallace, B. A., and Janes, R. W. (2001). Synchrotron radiation circular dichroism spectroscopy of proteins Secondary structure, fold recognition and structural genomics. Curr. Opin. Chem. Biol. 5, 567-571. 

PROTEIN FOLD RECOGNITION USING SEQUENCE PROFILES AND ITS APPLICATION IN STRUCTURAL GENOMICS... 

Montelione, G. T. (2001) Structural genomics an approach to the protein folding problem. Proc. Natl. Acad. Sci. USA 98, 13,488-13,489. 

The ability to recognize the way in which a protein sequence is folded in three dimensions should enable us to model the interactions of specific side-chains in a manner that is simply not possible when considering proteins entirely at the sequence level. This notion has resulted in sequence threading algorithms that assess the level of compatibility of a sequence with a database of fold patterns (65, 66). The principal downside to this approach is that novel structural types cannot be pre- dieted, because at least one example of each fold type must be present in the fold pattern database. Structural genomics may be the means whereby fold pattern databases can be populated with sufficient data to make them useful as predictive tools. 

The goal of structural genomics projects is to solve experimental structures of all major classes of protein folds systematically independent of some functional interest in the proteins [238, 239]. The aim is to chart the protein structure space efficiently. Functional annotations and/or assignment are made afterwards. 

In addition to conventional sequence motifs (Prosite, BLOCKS, PRINTS, etc.), the compilation of structural motifs indicative of specific functions from known structures has been proposed [268]. This should improve even the results obtained with multiple (one-dimensional sequence) patterns exploited in the BLOCKS and PRINTS databases. Recently, the use of models to define approximate structural motifs (sometimes called fuzzy functional forms, FFFs [269]) has been put forward to construct a library of such motifs enhancing the range of applicability of motif searches at the price of reduced sensitivity and specificity. Such approaches are supported by the fact that, often, active sites of proteins necessary for specific functions are much more conserved than the overall protein structure (e.g. bacterial and eukaryotic serine proteases), such that an inexact model could have a partly accurately conserved part responsible for function. As the structural genomics projects produce a more and more comprehensive picture of the structure space with representatives for all major protein folds and with the improved homology search methods linking the related sequences and structures to such representatives, comprehensive libraries of highly discriminative structural motifs are envisionable. 

Kuroda, Y., K. Tani, Y. Matsuo, and S. Yokoyama. 2000. Automated search of natively folded protein fragments for high-throughput structure determination in structural genomics. Protein Sci 9 2313-21. 

Threading If the sequence of a protein is completely dissimilar from the proteins of which the structure is known, structure prediction is often still possible by threading the sequence through a library of protein folds. All amino acids are evaluated and scored at all positions of this fold library and a best fold is chosen. It is estimated that 35% of all protein folds are currently known, but this percentage should rapidly increase because of structural genomics efforts. 

Structural genomics of yeast Yeast proteins, new folds Universite Paris-Sud ... 

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