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Structure paper

TitleOrthosteric and allosteric modulation of human HCAR2 signaling complex.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 7620, Year 2023
Publish dateNov 22, 2023
AuthorsChunyou Mao / Mengru Gao / Shao-Kun Zang / Yanqing Zhu / Dan-Dan Shen / Li-Nan Chen / Liu Yang / Zhiwei Wang / Huibing Zhang / Wei-Wei Wang / Qingya Shen / Yanhui Lu / Xin Ma / Yan Zhang /
PubMed AbstractHydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors ...Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.
External linksNat Commun / PubMed:37993467 / PubMed Central
MethodsEM (single particle)
Resolution2.55 - 2.76 Å
Structure data

36010

8j6p

EMDB-36010, PDB-8j6p:
Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex
Method: EM (single particle) / Resolution: 2.55 Å

36011

8j6q

EMDB-36011, PDB-8j6q:
Cryo-EM structure of the 3-HB and compound 9n-bound human HCAR2-Gi1 complex
Method: EM (single particle) / Resolution: 2.6 Å

36012

8j6r

EMDB-36012, PDB-8j6r:
Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex
Method: EM (single particle) / Resolution: 2.76 Å

Chemicals

ChemComp-IX8:
7-methyl-N-[(2R)-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-NIO:
NICOTINIC ACID / Niacin

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

ChemComp-HOH:
WATER / Water

ChemComp-3HR:
(3R)-3-hydroxybutanoic acid

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

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / hydroxycarboxylic acid receptor / Niacin / compound 9n / Class A GPCR / 3-HB / MK-6892

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