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

  • Nat Commun. 2023 Nov 6;14(1):7150. doi: 10.1038/s41467-023-42764-8.
Jae-Hyun Park  #  1 ,  Kouki Kawakami  #  2 ,  Naito Ishimoto  1 ,  Tatsuya Ikuta  2 ,  Mio Ohki  1 ,  Toru Ekimoto  3 ,  Mitsunori Ikeguchi  3  4 ,  Dong-Sun Lee  5 ,  Young-Ho Lee  6  7  8  9  10 ,  Jeremy R H Tame  1 ,  Asuka Inoue  11 ,  Sam-Yong Park  12
Affiliations
  • 1. Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama, 230-0045, Japan.
  • 2. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.
  • 3. Computational Life Science Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama City University, Tsurumi, Yokohama, 230-0045, Japan.
  • 4. HPC- and AI-driven Drug Development Platform Division, Center for Computational Science, RIKEN, Yokohama, 230-0045, Japan.
  • 5. Bio-Health Materials Core-Facility Center and Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju, 63243, Republic of Korea.
  • 6. Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, Chungbuk, 28119, Republic of Korea.
  • 7. Bio-Analytical Science, University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 8. Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 9. Department of Systems Biotechnology, Chung-Ang University, Gyeonggi, 17546, Republic of Korea.
  • 10. Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Miyagi, 980-8578, Japan.
  • 11. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan. [email protected].
  • 12. Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama, 230-0045, Japan. [email protected].
  • # Contributed equally.
PMID: 37932263 DOI: 10.1038/s41467-023-42764-8
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.