Original Article

Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1

Authors: LIU Shi-en1,2, HU Jun-chi1,2, ZHANG Hao1,2, XU Pan1,2, WAN Wei1,2, ZHENG Ming-yue1,2, YU Kun-qian1,2, DING Hong3, JIANG Hualiang1,2, ZHOU Lu4, LUO Cheng1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 School of Pharmacy, Fudan University, Shanghai 201203, China
Corresponding to: ZHOU Lu: zhoulu@fudan.edu.cn, LUO Cheng: cluo@mail.shcnc.ac.cn,
DOI: 10.1038/aps.2017.37
Received: 14 February 2017
Accepted: 9 March 2017
Advance online: 27 July 2017

Abstract

Abstract
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.
Keywords: phosphoglycerate mutase 1 (PGAM1); human cancers; metabolic target; C-terminal region; conformational changes; molecular dynamics simulation