The allosteric landscape of the Src kinase

Enzymes catalyze the reactions of life and are the targets of nearly all small molecule drugs. Most drugs inhibit enzymes by binding to conserved active sites, causing problems of specificity and toxicity. Targeting regulatory allosteric sites can increase specificity, overcome drug resistance and tune or activate activity.However, the vast majority of enzymes have no known allosteric sites and methods do not exist to globally identify or predict them.Here we present a general and fast method to globally chart allosteric communication in enzymes and apply it to the Src protein kinase to produce the first comprehensive map of negative and positive allosteric control of enzymatic activity. Allosteric control of Src is pervasive, anisotropic and distance dependent, but fairly predictable from simple sequence and structural features. The comprehensive allosteric map enables unbiased identification of all the allosterically active surface pockets of the Src kinase for the development of activatory and inhibitory drugs.This general approach can be used to chart global allosteric maps of many kinases, enzymes, and other biochemical activities important for medicine and biotechnology.酶催化生命体内的化学反应，亦是几乎所有小分子药物的作用靶点。多数药物通过结合保守活性位点抑制酶活性，由此引发特异性与毒性问题。靶向调控变构位点（allosteric site）可提升特异性、克服耐药性，并可调节或激活酶活性。然而，绝大多数酶尚未发现已知的变构位点，且目前尚无能够全局识别或预测此类位点的方法。本研究提出一种通用且快速的方法，可全局绘制酶中的变构通信（allosteric communication）图谱，并将其应用于Src蛋白激酶（Src protein kinase），首次获得了酶活性正负变构调控的全面图谱。Src的变构调控具有普遍性、各向异性且依赖距离，但可通过简单的序列与结构特征进行较为准确的预测。该全面变构图谱可实现无偏识别Src激酶的所有变构活性表面口袋，用于开发激活剂与抑制剂类药物。此通用方法可用于绘制众多与医药及生物技术相关的激酶、酶及其他生化活性的全局变构图谱。