EMD-33442

Single-particle
3.1 Å
EMD-33442 Deposition: 16/05/2022
Map released: 27/07/2022
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-33442

Serotonin 4 (5-HT4) receptor-Gs-Nb35 complex

EMD-33442

Single-particle
3.1 Å
EMD-33442 Deposition: 16/05/2022
Map released: 27/07/2022
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Lama glama
Sample: Serotonin 4 (5-HT4) receptor-Gs-Nb35 complex
Fitted models: 7xt8 (Avg. Q-score: 0.533)

Deposition Authors: Huang S, Xu P, Shen DD, Simon IA, Mao C, Tan Y, Zhang H, Harpsoe K , Li H, Zhang Y, You C, Yu X, Jiang Y, Zhang Y, Gloriam DE , Xu HE
GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.
Huang S, Xu P, Shen DD, Simon IA, Mao C, Tan Y, Zhang H, Harpsoe K , Li H, Zhang Y, You C, Yu X, Jiang Y, Zhang Y, Gloriam DE , Xu HE
(2022) Mol Cell , 82 , 2681 - 2695.e6
PUBMED: 35714614
DOI: doi:10.1016/j.molcel.2022.05.031
ISSN: 1097-2765
ASTM: MOCEFL
Abstract:
Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.