Structural genomics projects

The increased speed of structure determination necessary for the structural genomics projects makes an independent validation of the structures (by comparison to expected properties) particularly important. Structure validation helps to correct obvious errors (e.g. in the covalent structure) and leads to a more standardised representation of structural data, e.g. by agreeing on a common atom name nomenclature. The knowledge of the structure quality is a prerequisite for further use of the structure, e.g. in molecular modelling or drug design. 

Structural genomics is the systematic effort to gain a complete structural description of a defined set of molecules, ultimately for an organism s entire proteome. Structural genomics projects apply X-ray crystallography and NMR spectroscopy in a high-throughput manner. 

Stigmatization, disease-based, 75-77 Strict liability, 190, 191, 326-327 Structural Genomics Project, 41 Studies, federally funded, 280. See also Research... 

Many advances in these techniques have been suggested and employed in the last few years, mainly within the framework of structural genomics projects [8]. Nevertheless, since so many sequences of therapeutic or industrial interest are known, the gap between the number of known sequences and the number of known structures is widening. Thus, the need for a computational method enabling direct prediction of structure from sequence is greater than ever before. 

Resource for information on structural genomics projects and for keeping track of the current status (experimental structure status, structural assignments, models, annotations) for proteins... 

The following sections briefly discuss some results and trends in using structure prediction for remote homology detection especially in the genomic context, to aid the structural genomics projects, to further whole genome annotation and to exploit the sequence-to-structure-to-function paradigm for functional predictions. 

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. 

Recently, several successful individual structure-based functional predictions within the structural genomics projects have been reported an ATPase or ATP-mediated switch in one example [248], a new NTPase in M. jannaschii in a second example [249] and other test cases are the HIT family [250], E. coli ycaC [251], HdeA [252], and yjgF gene products [253], For a recent review on the current capabilities and prospects of function predictions from structure for bona fide hypothetical proteins on a genomewide scale, see [254]. 

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. 

This last case was indeed very rare until recently. The advent of structural genomics projects has resulted in an unprecedented number of protein structures deposited in the PDB identified as hypothetical proteins. The number of structures labeled as hypothetical protein or unknown function ranges from 30 to 60% of the total number of depositions depending on the structural genomics center, and this number is increasing exponentially. Currently, the number of structures of hypothetical proteins deposited in the PDB doubles every six months. 

Structural genomics projects were expected to provide clear evidence regarding the functions of hypothetical proteins and allow their functional annotation with minimal or no experimental poststructural analysis. It has been observed that the functions of hypothetical proteins can seldom be inferred exclusively from their structures. In fact, in a majority of cases structures provide only corroborating evidence for inconclusive annotations derived from sequence similarity searches. These observations argue for the need for increased efforts to characterize hypothetical proteins biochemically. 

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