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Structure paper

TitleInactive and active state structures template selective tools for the human 5-HT receptor.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 7, Page 677-687, Year 2022
Publish dateJul 14, 2022
AuthorsShicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan F Fay / Bryan L Roth /
PubMed AbstractSerotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 ...Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.
External linksNat Struct Mol Biol / PubMed:35835867 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.73 - 2.8 Å
Structure data

26597

7um5

EMDB-26597, PDB-7um5:
CryoEM structure of Go-coupled 5-HT5AR in complex with 5-CT
Method: EM (single particle) / Resolution: 2.73 Å

26598

7um6

EMDB-26598, PDB-7um6:
CryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride
Method: EM (single particle) / Resolution: 2.79 Å

26599

7um7

EMDB-26599, PDB-7um7:
CryoEM structure of Go-coupled 5-HT5AR in complex with Methylergometrine
Method: EM (single particle) / Resolution: 2.75 Å

PDB-7um4:
Crystal structure of inactive 5-HT5AR in complex with AS2674723
Method: X-RAY DIFFRACTION / Resolution: 2.8 Å

Chemicals

ChemComp-PGE:
TRIETHYLENE GLYCOL / Polyethylene glycol

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER / Diethylene glycol

ChemComp-PG4:
TETRAETHYLENE GLYCOL / precipitant*YM / Polyethylene glycol

ChemComp-1PE:
PENTAETHYLENE GLYCOL / precipitant*YM / Polyethylene glycol

ChemComp-NN6:
~{N}-[azanyl(azanylidene)methylidene]-5-fluoranyl-8-[2,4,6-tris(fluoranyl)phenyl]-3,4-dihydro-1~{H}-isoquinoline-2-carboxamide

ChemComp-HOH:
WATER / Water

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

ChemComp-H8G:
N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea / medication*YM / Lisuride

ChemComp-H8D:
(8beta)-N-[(2S)-1-hydroxybutan-2-yl]-6-methyl-9,10-didehydroergoline-8-carboxamide / medication*YM / Methylergometrine

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / inactive state / 5-HT5AR / HTR5A / 5-CT / active state / Go / Lisuride / Methylergometrine

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