Ling Baoping, Liu Yuxia, Li Xiaoping, Wang Zhiguo, Bi Siwei
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong Province, 273165, China.
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, China.
Proteins. 2016 Jun;84(6):792-802. doi: 10.1002/prot.25029. Epub 2016 Mar 25.
Malonyl-CoA decarboxylase (MCD) can control the level of malonyl-CoA in cell through the decarboxylation of malonyl-CoA to acetyl-CoA, and plays an essential role in regulating fatty acid metabolism, thus it is a potential target for drug discovery. However, the interactions of MCD with CoA derivatives are not well understood owing to unavailable crystal structure with a complete occupancy in the active site. To identify the active site of MCD, molecular docking and molecular dynamics simulations were performed to explore the interactions of human mitochondrial MCD (HmMCD) and CoA derivatives. The findings reveal that the active site of HmMCD indeed resides in the prominent groove which resembles that of CurA. However, the binding modes are slightly different from the one observed in CurA due to the occupancy of the side chain of Lys183 from the N-terminal helical domain instead of the adenine ring of CoA. The residues 300 - 305 play an essential role in maintaining the stability of complex mainly through hydrogen bond interactions with the pyrophosphate moiety of acetyl-CoA. Principle component analysis elucidates the conformational distribution and dominant concerted motions of HmMCD. MM_PBSA calculations present the crucial residues and the major driving force responsible for the binding of acetyl-CoA. These results provide useful information for understanding the interactions of HmMCD with CoA derivatives. Proteins 2016; 84:792-802. © 2016 Wiley Periodicals, Inc.
丙二酰辅酶A脱羧酶（MCD）可通过将丙二酰辅酶A脱羧生成乙酰辅酶A来控制细胞内丙二酰辅酶A的水平，在调节脂肪酸代谢中起重要作用，因此是药物研发的潜在靶点。然而，由于缺乏活性位点完全占据的晶体结构，MCD与辅酶A衍生物之间的相互作用尚未得到充分了解。为了确定MCD的活性位点，进行了分子对接和分子动力学模拟，以探究人线粒体MCD（HmMCD）与辅酶A衍生物之间的相互作用。研究结果表明，HmMCD的活性位点确实位于与CurA类似的突出凹槽中。然而，由于来自N端螺旋结构域的Lys183侧链占据了位置，而非辅酶A的腺嘌呤环，其结合模式与在CurA中观察到的略有不同。残基300 - 305主要通过与乙酰辅酶A的焦磷酸部分形成氢键相互作用，在维持复合物稳定性方面发挥重要作用。主成分分析阐明了HmMCD的构象分布和主要协同运动。MM_PBSA计算给出了负责乙酰辅酶A结合的关键残基和主要驱动力。这些结果为理解HmMCD与辅酶A衍生物之间的相互作用提供了有用信息。《蛋白质》2016年；84:792 - 802。© 2016威利期刊公司。
