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Issue 2, 2011
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Proteome-wide prediction of overlapping small molecule and protein binding sites using structure

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Abstract

Small molecules that modulate proteinprotein interactions are of great interest for chemical biology and therapeutics. Here I present a structure-based approach to predict ‘bi-functional’ sites able to bind both small molecule ligands and proteins, in proteins of unknown structure. First, I develop a homology-based annotation method that transfers binding sites of known three-dimensional structure onto protein sequences, predicting residues in ligand and protein binding sites with estimated true positive rates of 98% and 88%, respectively, at 1% false positive rates. Applying this method to the human proteome predicts 8463 proteins with bi-functional residues and correctly recovers the targets of known interaction modulators. Proteins with significantly (p < 0.01) more bi-functional residues than expected were found to be enriched in regulatory and depleted in metabolism functions. Finally, I demonstrate the utility of the method by describing examples of predicted overlap and evidence of their biological and therapeutic relevance. The results suggest that combining the structures of known binding sites with established fold detection algorithms can predict regions of proteinprotein interfaces that are amenable to small molecule modulation. Open-source software and the results for several complete proteomes are available at http://pibase.janelia.org/homolobind.

Graphical abstract: Proteome-wide prediction of overlapping small molecule and protein binding sites using structure

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Publication details

The article was received on 17 Sep 2010, accepted on 11 Oct 2010 and first published on 24 Nov 2010


Article type: Paper
DOI: 10.1039/C0MB00200C
Citation: Mol. BioSyst., 2011,7, 545-557
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    Proteome-wide prediction of overlapping small molecule and protein binding sites using structure

    F. P. Davis, Mol. BioSyst., 2011, 7, 545
    DOI: 10.1039/C0MB00200C

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