Arif M, Pradhan Suman Kalyan, Thanuja G R, Vedamurthy B M, Agrawal Shipra, Dasgupta Dipak, Kundu Tapas K
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India.
J Med Chem. 2009 Jan 22;52(2):267-77. doi: 10.1021/jm800657z.
Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, diabetes, and asthma. Therefore, small molecule inhibitors and activators of HATs are being considered as new generation therapeutics. Here, we report the molecular mechanisms of p300 HAT inhibition by specific and nonspecific HAT inhibitors: garcinol, isogarcinol, and 1 (LTK14). The p300 specific HAT inhibitor 1 behaves as a noncompetitive inhibitor for both acetyl-CoA and histone, unlike nonspecific HAT inhibitors garcinol and isogarcinol. The isothermal calorimetric data suggest that there is a high affinity enthalpy driven single binding site for 1 on p300HAT domain in contrast to two binding sites for garcinol and isogarcinol. Furthermore, the precise nature of molecular interactions was determined by using fluorescence, docking, and mutational studies. On the basis of these observations, we have proposed the mechanisms of specific versus nonspecific HAT inhibition by these small molecule compounds, which may be useful to design therapeutically favorable HAT inhibitors.
组蛋白乙酰转移酶（HATs）功能障碍会引发多种疾病，包括癌症、糖尿病和哮喘。因此，HATs的小分子抑制剂和激活剂正被视为新一代治疗药物。在此，我们报告了特异性和非特异性HAT抑制剂（藤黄醇、异藤黄醇和1（LTK14））对p300 HAT的抑制分子机制。与非特异性HAT抑制剂藤黄醇和异藤黄醇不同，p300特异性HAT抑制剂1对乙酰辅酶A和组蛋白均表现为非竞争性抑制剂。等温滴定量热数据表明，1在p300HAT结构域上有一个高亲和力的焓驱动单一结合位点，而藤黄醇和异藤黄醇有两个结合位点。此外，通过荧光、对接和突变研究确定了分子相互作用的确切性质。基于这些观察结果，我们提出了这些小分子化合物特异性与非特异性抑制HAT的机制，这可能有助于设计治疗效果良好的HAT抑制剂。
