Abstract
BackgroundThe prediction of biochemical function from the 3D structure of a protein has proved to be much more difficult than was originally foreseen. A reliable method to test the likelihood of putative annotations and to predict function from structure would add tremendous value to structural genomics data. We report on a new method, Structurally Aligned Local Sites of Activity (SALSA), for the prediction of biochemical function based on a local structural match at the predicted catalytic or binding site.ResultsImplementation of the SALSA method is described. For the structural genomics protein PY01515 (PDB ID 2aqw) from Plasmodium yoelii, it is shown that the putative annotation, Orotidine 5'-monophosphate decarboxylase (OMPDC), is most likely correct. SALSA analysis of YP_001304206.1 (PDB ID 3h3l), a putative sugar hydrolase from Parabacteroides distasonis, shows that its active site does not bear close resemblance to any previously characterized member of its superfamily, the Concanavalin A-like lectins/glucanases. It is noted that three residues in the active site of the thermophilic beta-1,4-xylanase from Nonomuraea flexuosa (PDB ID 1m4w), Y78, E87, and E176, overlap with POOL-predicted residues of similar type, Y168, D153, and E232, in YP_001304206.1. The substrate recognition regions of the two proteins are rather different, suggesting that YP_001304206.1 is a new functional type within the superfamily. A structural genomics protein from Mycobacterium avium (PDB ID 3q1t) has been reported to be an enoyl-CoA hydratase (ECH), but SALSA analysis shows a poor match between the predicted residues for the SG protein and those of known ECHs. A better local structural match is obtained with Anabaena beta-diketone hydrolase (ABDH), a known β-diketone hydrolase from Cyanobacterium anabaena (PDB ID 2j5s). This suggests that the reported ECH function of the SG protein is incorrect and that it is more likely a β-diketone hydrolase.ConclusionsA local site match provides a more compelling function prediction than that obtainable from a simple 3D structure match. The present method can confirm putative annotations, identify misannotation, and in some cases suggest a more probable annotation.
Highlights
The prediction of biochemical function from the 3D structure of a protein has proved to be much more difficult than was originally foreseen
Orotidine 5’-monophosphate decarboxylase (OMPDC) is a member of the ribulose phosphate binding barrel (RPBB) superfamily and has a TIM barrel [33] structure, with the active site located inside the beta barrel, spanning the eight beta strands
For any given protein structure of previously characterized function, the list of residues reported in the literature to be important for the biochemical function is a subset of the list of residues predicted by Partial Order Optimum Likelihood (POOL)
Summary
The prediction of biochemical function from the 3D structure of a protein has proved to be much more difficult than was originally foreseen. A reliable method to test the likelihood of putative annotations and to predict function from structure would add tremendous value to structural genomics data. Overviews of current methods for the functional annotation of proteins from their sequence and/or structure have been given in recent reviews [5,6,7,8]. The simplest, and most commonly employed [6] methods seek the closest sequence matches using a search program such as BLAST [9], or alternatively the closest 3D structure match obtained from e.g. Dali [10], Combinatorial Extension (CE) [11], or Topofit [12], and just transfer the function from the closest match to the query protein. The aim of this work is to exploit structural information, together with computed chemical properties, to enhance function prediction capabilities
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