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Structure paper

TitleStructure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 1939, Year 2024
Publish dateMar 2, 2024
AuthorsManish K Yadav / Parishmita Sarma / Jagannath Maharana / Manisankar Ganguly / Sudha Mishra / Nashrah Zaidi / Annu Dalal / Vinay Singh / Sayantan Saha / Gargi Mahajan / Saloni Sharma / Mohamed Chami / Ramanuj Banerjee / Arun K Shukla /
PubMed AbstractThe Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. ...The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor.
External linksNat Commun / PubMed:38431681 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.75 Å
Structure data

35817

8iy9

EMDB-35817, PDB-8iy9:
Structure of Niacin-GPR109A-G protein complex
Method: EM (single particle) / Resolution: 3.37 Å

35822

8iyh

EMDB-35822, PDB-8iyh:
Structure of MK6892-GPR109A-G-protein complex
Method: EM (single particle) / Resolution: 3.3 Å

35831

8iyw

EMDB-35831, PDB-8iyw:
Structure of GSK256073-GPR109A-G-protein complex
Method: EM (single particle) / Resolution: 3.45 Å

36193

8jer

EMDB-36193, PDB-8jer:
Structure of Acipimox-GPR109A-G protein complex
Method: EM (single particle) / Resolution: 3.45 Å

36280

8jhn

EMDB-36280, PDB-8jhn:
Structure of MMF-GPR109A-G protein complex
Method: EM (single particle) / Resolution: 3.75 Å

Chemicals

ChemComp-NIO:
NICOTINIC 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

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

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


ChemComp, No image

ChemComp-UR9:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / GPCR / G protein

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