Leroux Alejandro E, Biondi Ricardo M
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET, Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET, Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina; Department of Internal Medicine I, University Hospital, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; DKTK German Cancer Consortium (DKTK), Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Trends Biochem Sci. 2020 Jan;45(1):27-41. doi: 10.1016/j.tibs.2019.09.007. Epub 2019 Nov 2.
Protein-protein interactions often regulate the activity of protein kinases by allosterically modulating the conformation of the ATP-binding site. Bidirectional allostery implies that reverse modulation (i.e., from the ATP-binding site to the interaction and regulatory sites) must also be possible. Here, we review both the allosteric regulation of protein kinases and recent work describing how compounds binding at the ATP-binding site can promote or inhibit protein kinase interactions at regulatory sites via the reverse mechanism. Notably, the pharmaceutical industry has been developing compounds that bind to the ATP-binding site of protein kinases and potently disrupt protein-protein interactions between target protein kinases and their regulatory interacting partners. Learning to modulate allosteric processes will facilitate the development of protein-protein interaction modulators.
蛋白质-蛋白质相互作用通常通过变构调节ATP结合位点的构象来调控蛋白激酶的活性。双向变构意味着反向调节（即从ATP结合位点到相互作用和调节位点）也必定是可能的。在此，我们综述了蛋白激酶的变构调节以及近期的研究工作，这些研究描述了结合于ATP结合位点的化合物如何通过反向机制促进或抑制调节位点处的蛋白激酶相互作用。值得注意的是，制药行业一直在研发结合于蛋白激酶ATP结合位点并有效破坏目标蛋白激酶与其调节相互作用伴侣之间蛋白质-蛋白质相互作用的化合物。学会调节变构过程将有助于蛋白质-蛋白质相互作用调节剂的开发。
