7XTB

Serotonin 6 (5-HT6) receptor-Gs-Nb35 complex

Summary for 7XTB

• Entry DOI: 10.2210/pdb7xtb/pdb
• EMDB information: 33445
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, serotonin receptor, 5-ht, 5-ht6 receptor, signaling complex, cryo-em structure, ligand selectivity, g protein selectivity, structure-function relationships, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 170318.40

Authors

Huang, S.,Xu, P.,Shen, D.D.,Simon, I.A.,Mao, C.,Tan, Y.,Zhang, H.,Harpsoe, K.,Li, H.,Zhang, Y.,You, C.,Yu, X.,Jiang, Y.,Zhang, Y.,Gloriam, D.E.,Xu, H.E. (deposition date: 2022-05-16, release date: 2022-07-27, Last modification date: 2024-10-23)

Primary citation

Huang, S.,Xu, P.,Shen, D.D.,Simon, I.A.,Mao, C.,Tan, Y.,Zhang, H.,Harpsoe, K.,Li, H.,Zhang, Y.,You, C.,Yu, X.,Jiang, Y.,Zhang, Y.,Gloriam, D.E.,Xu, H.E.
GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.
Mol.Cell, 82:2681-2695.e6, 2022

PubMed Abstract: Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G, G or G proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT, 5-HT, and 5-HT with G, and 5-HT with G. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G and G, 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 G or G. Together, these results present a common mechanism of G versus G protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.

PubMed: 35714614
DOI: 10.1016/j.molcel.2022.05.031

Experimental method

ELECTRON MICROSCOPY (3.3 Å)