Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

Jae-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 () and Sam-Yong Park ()
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Jae-Hyun Park: Yokohama City University
Kouki Kawakami: Tohoku University
Naito Ishimoto: Yokohama City University
Tatsuya Ikuta: Tohoku University
Mio Ohki: Yokohama City University
Toru Ekimoto: Yokohama City University, Yokohama City University
Mitsunori Ikeguchi: Yokohama City University, Yokohama City University
Dong-Sun Lee: Jeju National University
Young-Ho Lee: Korea Basic Science Institute
Jeremy R. H. Tame: Yokohama City University
Asuka Inoue: Tohoku University
Sam-Yong Park: Yokohama City University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce Gi/o 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 Gi-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2–Gi 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.

Date: 2023
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DOI: 10.1038/s41467-023-42764-8

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