EMD-33442
Serotonin 4 (5-HT4) receptor-Gs-Nb35 complex
EMD-33442
Single-particle3.1 Å
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Map released: 27/07/2022
Last modified: 23/10/2024
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
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
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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
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(2022) Mol Cell , 82 , 2681 - 2695.e6
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.
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.