Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Ying Wang; Mingyu Li; Wenqi Liang; Xinchao Shi; Jigang Fan; Ren Kong; Yaqin Liu; Jian Zhang; Ting Chen; Shaoyong Lu

doi:10.1016/j.csbj.2022.01.015

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Comput Struct Biotechnol J. 2022 Jan 20:20:628-639. doi: 10.1016/j.csbj.2022.01.015. eCollection 2022.

Authors

Ying Wang^{1

2}, Mingyu Li¹, Wenqi Liang³, Xinchao Shi¹, Jigang Fan¹, Ren Kong⁴, Yaqin Liu², Jian Zhang^{1

2}, Ting Chen⁵, Shaoyong Lu^{1

2}

Affiliations

¹ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
² Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
³ Department of Emergency, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
⁴ Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China.
⁵ Department of Cardiology, Changzheng Hospital, Naval Medical University, Shanghai 200023, China.

Abstract

Class B G protein-coupled receptors (GPCRs) are important targets in the treatment of metabolic syndrome and diabetes. Although multiple structures of class B GPCRs-G protein complexes have been elucidated, the detailed activation mechanism of the receptors remains unclear. Here, we combine Gaussian accelerated molecular dynamics simulations and Markov state models (MSM) to investigate the activation mechanism of a canonical class B GPCR, human glucagon receptor-GCGR, including the negative allosteric modulator-bound inactive state, the agonist glucagon-bound active state, and both glucagon- and Gs-bound fully active state. The free-energy landscapes of GCGR show the conformational ensemble consisting of three activation-associated states: inactive, active, and fully active. The structural analysis indicates the high dynamics of GCGR upon glucagon binding with both active and inactive conformations in the ensemble. Significantly, the H8 and TM6 exhibits distinct features from the inactive to the active states. The additional simulations demonstrate the role of H8 in the recruitment of Gs. Gs binding presents a crucial function of stabilizing the glucagon binding site and MSM highlights the absolute requirement of Gs to help the GCGR reach the fully active state. Together, our results reveal the detailed activation mechanism of GCGR from the view of conformational dynamics.

Keywords: Allosteric modulator; GPCR; Markov state model; Molecular dynamics simulations.