Functional Coverage of the Human Genome by Existing Structures, Structural Genomics Targets, and Homology Models

Abstract

The bias in protein structure and function space resulting from experimental limitations and targeting of particular functional classes of proteins by structural biologists has long been recognized, but never continuously quantified. Using the Enzyme Commission and the Gene Ontology classifications as a reference frame, and integrating structure data from the Protein Data Bank (PDB), target sequences from the structural genomics projects, structure homology derived from the SUPERFAMILY database, and genome annotations from Ensembl and NCBI, we provide a quantified view, both at the domain and whole-protein levels, of the current and projected coverage of protein structure and function space relative to the human genome. Protein structures currently provide at least one domain that covers 37% of the functional classes identified in the genome; whole structure coverage exists for 25% of the genome. If all the structural genomics targets were solved (twice the current number of structures in the PDB), it is estimated that structures of one domain would cover 69% of the functional classes identified and complete structure coverage would be 44%. Homology models from existing experimental structures extend the 37% coverage to 56% of the genome as single domains and 25% to 31% for complete structures. Coverage from homology models is not evenly distributed by protein family, reflecting differing degrees of sequence and structure divergence within families. While these data provide coverage, conversely, they also systematically highlight functional classes of proteins for which structures should be determined. Current key functional families without structure representation are highlighted here; updated information on the “most wanted list” that should be solved is available on a weekly basis from http://function.rcsb.org:8080/pdb/function_distribution/index.html. The sequencing of the human genome provides biologists with new opportunities to understand the molecular basis of physiological processes and disease states. To take full advantage of these opportunities, the three-dimensional structures of the gene products are needed to provide the appropriate level of detail. Since protein structure determination lags behind protein sequence determination, an important and ongoing question becomes: what degree of coverage of the human proteome do we have from experimental structures, and what can we infer by modeling? Or, turning the question around: what structures do we need to determine (the “most wanted list”) to further our understanding of the human condition? This paper addresses these questions through integration of existing data resources correlated using comparative functional features, namely the Gene Ontology, which describes biochemical process, molecular function, and cellular location for all types of proteins, and the Enzyme Commission classification for enzymes. Genetic disease states are linked through the Online Mendelian Inheritance in Man resource. Readers can ask their own questions of the resource at http://function.rcsb.org:8080/pdb/function_distribution/index.html. The resource should prove particularly useful to the structural genomics community as it strives to undertake large-scale structure determination with a goal of improving the understanding of protein functional space.