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Structure paper

TitleStructural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 7150, Year 2023
Publish dateNov 6, 2023
AuthorsJae-Hyun Park / Kouki Kawakami / Naito Ishimoto / Tatsuya Ikuta / Mio Ohki / Toru Ekimoto / Mitsunori Ikeguchi / Dong-Sun Lee / Young-Ho Lee / Jeremy R H Tame / Asuka Inoue / Sam-Yong Park /
PubMed AbstractHydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with ...Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced G-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-G signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation.
External linksNat Commun / PubMed:37932263 / PubMed Central
MethodsEM (single particle)
Resolution2.77 - 3.74 Å
Structure data

35234

8i7v

EMDB-35234, PDB-8i7v:
Cryo-EM structure of Acipimox bound human hydroxy-carboxylic acid receptor 2 in complex with Gi heterotrimer
Method: EM (single particle) / Resolution: 2.77 Å

35235

8i7w

EMDB-35235, PDB-8i7w:
Cryo-EM structure of GSK256073 bound human hydroxy-carboxylic acid receptor 2 in complex with Gi heterotrimer
Method: EM (single particle) / Resolution: 3.39 Å

36900

8k5b

EMDB-36900, PDB-8k5b:
Cryo-EM structure of niacin bound human hydroxy-carboxylic acid receptor 2 (Local refinement)
Method: EM (single particle) / Resolution: 3.43 Å

36901

8k5c

EMDB-36901, PDB-8k5c:
Cryo-EM structure of Acipimox bound human hydroxy-carboxylic acid receptor 2 (Local refinement)
Method: EM (single particle) / Resolution: 3.13 Å

36902

8k5d

EMDB-36902, PDB-8k5d:
Cryo-EM structure of GSK256073 bound human hydroxy-carboxylic acid receptor 2 (Local refinement)
Method: EM (single particle) / Resolution: 3.74 Å

Chemicals

ChemComp-OJX:
5-methyl-4-oxidanyl-pyrazin-4-ium-2-carboxylic acid

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

ChemComp-NIO:
NICOTINIC ACID

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / G-Protein / acipimox / signaling

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