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Structure paper

TitleStructural basis for partial agonism in 5-HT receptors.
Journal, issue, pagesNat Struct Mol Biol, Vol. 31, Issue 4, Page 598-609, Year 2024
Publish dateJan 4, 2024
AuthorsKevin Felt / Madeleine Stauffer / Leslie Salas-Estrada / Peter R Guzzo / Dejian Xie / Jinkun Huang / Marta Filizola / Sudha Chakrapani /
PubMed AbstractHyperactivity of serotonin 3 receptors (5-HTR) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity ...Hyperactivity of serotonin 3 receptors (5-HTR) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity competitive antagonists, are used in the treatment of these conditions. Although generally effective for chemotherapy-induced nausea and vomiting, the use of setrons for treating irritable bowel syndrome has been impaired by adverse side effects. Partial agonists are now being considered as an alternative strategy, with potentially less severe side effects than full antagonists. However, a structural understanding of how these ligands work is lacking. Here, we present high-resolution cryogenic electron microscopy structures of the mouse 5-HTR in complex with partial agonists (SMP-100 and ALB-148471) captured in pre-activated and open-like conformational states. Molecular dynamics simulations were used to assess the stability of drug-binding poses and interactions with the receptor over time. Together, these studies reveal mechanisms for the functional differences between orthosteric partial agonists, full agonists and antagonists of the 5-HTR.
External linksNat Struct Mol Biol / PubMed:38177669
MethodsEM (single particle)
Resolution2.7 - 3.79 Å
Structure data

29409

8frw

EMDB-29409, PDB-8frw:
Full-length mouse 5-HT3A receptor in complex with ALB148471, pre-activated
Method: EM (single particle) / Resolution: 2.92 Å

29410

8frx

EMDB-29410, PDB-8frx:
Full-length mouse 5-HT3A receptor in complex with SMP100, pre-activated
Method: EM (single particle) / Resolution: 2.7 Å

29411

8frz

EMDB-29411, PDB-8frz:
Full-length mouse 5-HT3A receptor in complex with serotonin, pre-activated
Method: EM (single particle) / Resolution: 2.75 Å

29418

8fsb

EMDB-29418, PDB-8fsb:
Full-length mouse 5-HT3A receptor in complex with serotonin, open-like
Method: EM (single particle) / Resolution: 2.75 Å

29421

8fsp

EMDB-29421, PDB-8fsp:
Full-length mouse 5-HT3A receptor in complex with SMP100, open-like
Method: EM (single particle) / Resolution: 3.79 Å

29422

8fsz

EMDB-29422, PDB-8fsz:
Full-length mouse 5-HT3A receptor in complex with ALB148471, open-like
Method: EM (single particle) / Resolution: 3.79 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-Y7H:
5-[(1R,3S,5R)-1-azabicyclo[3.2.2]nonan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one

ChemComp-HOH:
WATER

ChemComp-Y82:
5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM

Source
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Partial agonist / cys-loop / pLGIC / ion channel / agonist

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