State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Acta Pharmacol Sin. 2017 Dec;38(12):1673-1682. doi: 10.1038/aps.2017.37. Epub 2017 Jul 27.
Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle. Using the PONDR-FIT server, we demonstrated that the C-terminal region was intrinsically disordered. We applied the Monte Carlo (MC) method to explore the conformational space of the C-terminus and conducted a series of explicit-solvent molecular dynamics (MD) simulations, and revealed that the C-terminal region is inherently dynamic; large-scale conformational changes in the C-terminal segment led to the structural transition of PGAM1 from the closed state to the open state. Furthermore, the C-terminal segment influenced 2,3-bisphosphoglycerate (2,3-BPG) binding. The proposed swing model illustrated a critical role of the C-terminus in the catalytic cycle through the conformational changes. In conclusion, the C-terminal region induces large movements of PGAM1 from the closed state to the open state and influences cofactor binding during the catalytic cycle. This report describes the dynamic features of the C-terminal region in detail and should aid in design of novel and efficient inhibitors of PGAM1. A swing mechanism of the C-terminal region is proposed, to facilitate further studies of the catalytic mechanism and the physiological functions of its homologues.
磷酸甘油酸变位酶 1（PGAM1）是糖酵解过程中的一种重要酶，在许多人类癌症中过度表达，因此被认为是癌症治疗有前途的代谢靶点。现有 PGAM1 及其同源蛋白晶体结构的 C 端部分部分无序，这一点可从弱电子密度得到证明。在这项研究中，我们确定了 PGAM1 的 C 端区域的构象行为及其在催化循环中的作用。使用 PONDR-FIT 服务器，我们证明了 C 端区域是固有无序的。我们应用蒙特卡罗（MC）方法探索 C 末端的构象空间，并进行了一系列的显式溶剂分子动力学（MD）模拟，结果表明 C 末端区域是固有动态的；C 末端片段的大规模构象变化导致 PGAM1 从关闭状态到打开状态的结构转变。此外，C 末端片段影响 2,3-双磷酸甘油酸（2,3-BPG）的结合。所提出的摆动模型通过构象变化说明了 C 末端在催化循环中的关键作用。总之，C 末端区域通过构象变化诱导 PGAM1 从关闭状态到打开状态的大规模运动，并影响催化循环中的辅助因子结合。本报告详细描述了 C 末端区域的动态特征，这有助于设计新型有效的 PGAM1 抑制剂。提出了 C 末端区域的摆动机制，以促进对其同源物的催化机制和生理功能的进一步研究。
