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Structure paper

TitleStructural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5899, Year 2023
Publish dateSep 22, 2023
AuthorsShota Suzuki / Kotaro Tanaka / Kouki Nishikawa / Hiroshi Suzuki / Atsunori Oshima / Yoshinori Fujiyoshi /
PubMed AbstractHydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only ...Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms.
External linksNat Commun / PubMed:37736747 / PubMed Central
MethodsEM (single particle)
Resolution2.85 - 3.21 Å
Structure data

EMDB-35442, PDB-8ihb:
Cryo-EM structure of HCA2-Gi complex with GSK256073
Method: EM (single particle) / Resolution: 2.85 Å

EMDB-35443, PDB-8ihf:
Cryo-EM structure of HCA2-Gi complex with MK6892
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-35444, PDB-8ihh:
Cryo-EM structure of HCA2-Gi complex with LUF6283
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-35445, PDB-8ihi:
Cryo-EM structure of HCA2-Gi complex with acifran
Method: EM (single particle) / Resolution: 3.11 Å

EMDB-35446, PDB-8ihj:
Cryo-EM structure of HCA3-Gi complex with acifran
Method: EM (single particle) / Resolution: 3.07 Å

EMDB-35447, PDB-8ihk:
Cryo-EM structure of HCA3-Gi complex with acifran (local)
Method: EM (single particle) / Resolution: 3.21 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-OKL:
8-chloranyl-3-pentyl-7H-purine-2,6-dione

ChemComp-FI7:
2-[[2,2-dimethyl-3-[3-(5-oxidanylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic acid

ChemComp-P8A:
5-butyl-1~{H}-pyrazole-3-carboxylic acid

ChemComp-P9X:
(5~{S})-5-methyl-4-oxidanylidene-5-phenyl-furan-2-carboxylic acid

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN / GPCR

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