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.

Functional impact of missense variants in BRCA1 predicted by supervised learning

“…The SNPs were classified with a support vector machine trained on amino acid residue substitutions from more than 1,500 human proteins. Because X-ray crystal structures are not available for most human proteins [77], we built homology models with an automated modeling pipeline MODPIPE that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building, and model assessment [78]. A small number of these predictions have been validated by biochemical and epidemiological studies found in the literature.…”

Exploring the structure and function paradigm

“…Consequently, the four major PSI Centres have targeted large sequence families that are most likely to adopt novel structures [1] (http://www.structuralgenomics.org), although these often have little or no functional annotation [3]. To maximise the biomedical benefit of PSI structures, recent reviews have proposed broadening selection criteria to explicitly focus on the relevance to human disease [4] or to provide structural characterisation of families with known functions [5]. Figure 1 shows that as the international genomics initiatives gather pace, both the number of sequences and protein families is still growing at an exponential rate, although the rate of expansion of protein families is substantially less.…”

Targeting the Human Cancer Pathway Protein Interaction Network by Structural Genomics

“…Overall HCPIN has 78% (45%), 46% (20%) single domain (residue) coverage at medium and high accuracy modeling levels, respectively. This single domain coverage of HCPIN proteins is significantly higher than the estimated average single domain coverage of the human proteome (27).…”

“…Although this cutoff is somewhat arbitrary, models generated from such templates will usually be of high reliability and accuracy. Such high quality structures or models of these human proteins are potentially useful for active site docking, studying catalytic mechanism, and designing ligands useful for drug discovery (67 (27), i.e. either an experimental structure or a structure template useful for medium accuracy modeling of at least part of the protein structure.…”

“…Recently Xie and Bourne (27) have discussed the structural coverage of human proteins grouped by the Enzyme Commission and the Gene Ontology classifications. This analysis provides a valuable summary of the structural information available for many human disease-related proteins and provides guidance for protein target selection by structural genomics projects.…”