Molecular Determinant Underlying Selective Coupling of Primary G‐Protein by Class A GPCRs
Qingya Shen, Xinyan Tang, Xin Wen, Shizhuo Cheng, Peng Xiao, Shao‐Kun Zang, Dandan Shen, Lei Jiang, Yanrong Zheng, Huibing Zhang, Haomang Xu, Chunyou Mao, Min Zhang, Weiwei Hu, Jin‐Peng Sun, Yan Zhang, Zhong Chen
Abstract
Abstract G‐protein‐coupled receptors (GPCRs) transmit downstream signals predominantly via G‐protein pathways. However, the conformational basis of selective coupling of primary G‐protein remains elusive. Histamine receptors H 2 R and H 3 R couple with G s ‐ or G i ‐proteins respectively. Here, three cryo‐EM structures of H 2 R‐G s and H 3 R‐G i complexes are presented at a global resolution of 2.6‐2.7 Å. These structures reveal the unique binding pose for endogenous histamine in H 3 R, wherein the amino group interacts with E206 5.46 of H 3 R instead of the conserved D114 3.32 of other aminergic receptors. Furthermore, comparative analysis of the H 2 R‐G s and H 3 R‐G i complexes reveals that the structural geometry of TM5/TM6 determines the primary G‐protein selectivity in histamine receptors. Machine learning (ML)‐based structuromic profiling and functional analysis of class A GPCR–G‐protein complexes illustrate that TM5 length, TM5 tilt, and TM6 outward movement are key determinants of the G s and G i/o selectivity among the whole Class A family. Collectively, the findings uncover the common structural geometry within class A GPCRs that determines the primary G s ‐ and G i/o ‐coupling selectivity.