Structural insights into adhesion GPCR ADGRL3 activation and Gq, Gs, Gi, and G12 coupling

Yu Qian; Zhengxiong Ma; Chunhong Liu; Xinzhi Li; Xinyan Zhu; Na Wang; Zhenmei Xu; Ruixue Xia; Jiale Liang; Yaning Duan; Han Yin; Yangjie Xiong; Anqi Zhang; Changyou Guo; Zheng Chen; Zhiwei Huang; Yuanzheng He

doi:10.1016/j.molcel.2022.10.009

Structural insights into adhesion GPCR ADGRL3 activation and G_q, G_s, G_i, and G₁₂ coupling

Mol Cell. 2022 Nov 17;82(22):4340-4352.e6. doi: 10.1016/j.molcel.2022.10.009. Epub 2022 Oct 28.

Authors

Yu Qian¹, Zhengxiong Ma², Chunhong Liu³, Xinzhi Li³, Xinyan Zhu², Na Wang², Zhenmei Xu², Ruixue Xia², Jiale Liang², Yaning Duan², Han Yin², Yangjie Xiong², Anqi Zhang³, Changyou Guo³, Zheng Chen³, Zhiwei Huang³, Yuanzheng He⁴

Affiliations

¹ Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology, Harbin 150001, China; HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
² Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology, Harbin 150001, China.
³ HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
⁴ Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology, Harbin 150001, China. Electronic address: ajian.he@hit.edu.cn.

PMID: 36309016
DOI: 10.1016/j.molcel.2022.10.009

Abstract

Adhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism remains obscure. Here, we present cryoelectron microscopy (cryo-EM) structures of ADGRL3 in complex with G_q, G_s, G_i, and G₁₂. The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. The structures also reveal the uncharted structural information of GPCR/G₁₂ coupling. A comparison of G_q, G_s, G_i, and G₁₂ engagements with ADGRL3 reveals the key determinant of G-protein coupling on the far end of αH5 of Gα. A detailed analysis of the engagements allows us to design mutations that specifically enhance one pathway over others. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity.

Keywords: ADGRL3; G(12) coupling; G-protein-coupling selectivity; aGPCR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy
GTP-Binding Proteins* / metabolism
Ligands
Receptors, G-Protein-Coupled* / metabolism

Substances

Ligands
Receptors, G-Protein-Coupled
GTP-Binding Proteins