Davis Fred P
Howard Hughes Medical Institute, Janelia Farm Research Campus, 19700 Helix Dr, Ashburn, VA 20147, USA.
Mol Biosyst. 2011 Feb;7(2):545-57. doi: 10.1039/c0mb00200c. Epub 2010 Nov 24.
Small molecules that modulate protein-protein 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 protein-protein 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.
调节蛋白质-蛋白质相互作用的小分子对于化学生物学和治疗学具有重要意义。在此，我提出一种基于结构的方法，用于预测未知结构蛋白质中能够结合小分子配体和蛋白质的“双功能”位点。首先，我开发了一种基于同源性的注释方法，将已知三维结构的结合位点转移到蛋白质序列上，在1%的假阳性率下，预测配体和蛋白质结合位点中的残基，估计真阳性率分别为98%和88%。将该方法应用于人类蛋白质组，预测出8463个具有双功能残基的蛋白质，并正确找回了已知相互作用调节剂的靶点。发现具有比预期显著更多（p < 0.01）双功能残基的蛋白质在调节功能中富集，而在代谢功能中减少。最后，我通过描述预测重叠的例子及其生物学和治疗相关性的证据来证明该方法的实用性。结果表明，将已知结合位点的结构与既定的折叠检测算法相结合，可以预测适合小分子调节的蛋白质-蛋白质界面区域。开源软件和几个完整蛋白质组的结果可在http://pibase.janelia.org/homolobind获取。
