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TitleGPCRs steer G and G selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.
Journal, issue, pagesMol Cell, Vol. 82, Issue 14, Page 2681-22695.e6, Year 2022
Publish dateJul 21, 2022
AuthorsSijie Huang / Peiyu Xu / Dan-Dan Shen / Icaro A Simon / Chunyou Mao / Yangxia Tan / Huibing Zhang / Kasper Harpsøe / Huadong Li / Yumu Zhang / Chongzhao You / Xuekui Yu / Yi Jiang / Yan Zhang / David E Gloriam / H Eric Xu /
PubMed AbstractSerotonin (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 ...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.
External linksMol Cell / PubMed:35714614
MethodsEM (single particle)
Resolution3.1 - 3.3 Å
Structure data

33442

7xt8

EMDB-33442, PDB-7xt8:
Serotonin 4 (5-HT4) receptor-Gs-Nb35 complex
Method: EM (single particle) / Resolution: 3.1 Å

33443

7xt9

EMDB-33443, PDB-7xt9:
Serotonin 4 (5-HT4) receptor-Gs complex
Method: EM (single particle) / Resolution: 3.2 Å

33444

7xta

EMDB-33444, PDB-7xta:
Serotonin 4 (5-HT4) receptor-Gi-scFv16 complex
Method: EM (single particle) / Resolution: 3.2 Å

33445

7xtb

EMDB-33445, PDB-7xtb:
Serotonin 6 (5-HT6) receptor-Gs-Nb35 complex
Method: EM (single particle) / Resolution: 3.3 Å

33446

7xtc

EMDB-33446, PDB-7xtc:
Serotonin 7 (5-HT7) receptor-Gs-Nb35 complex
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM / Serotonin

ChemComp-8K3:
3-(2-azanylethyl)-1H-indole-5-carboxamide / neurotransmitter, agonist*YM / 5-Carboxamidotryptamine

Source
  • homo sapiens (human)
  • lama glama (llama)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / serotonin receptor / 5-HT / 5-HT4 receptor / signaling complex / cryo-EM structure / ligand selectivity / G protein selectivity / structure-function relationships / 5-HT6 receptor / 5-HT7 receptor

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