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Structural insights into the human niacin receptor HCA2-Gi signalling complex.

<div class='caption-title'>Cryo-EM structure and binding pocket of HCA2-Gi complex.</div>
<div class='caption-title'>HCA2 activation and conformation changes.</div>
<div class='caption-title'>Comparison of HCA2-Gi complex with CB1-Gi complex in Gi protein binding.</div>
Yang Y, Kang HJ, Gao R, Wang J, Han GW, DiBerto JF, Wu L, Tong J, Qu L, Wu Y, Pileski R, Li X, Zhang XC, Zhao S, Kenakin T, Wang Q, Stevens RC, Peng W, Roth BL, Rao Z, Liu ZJ
OpenAccess logo Nat Commun 14 1692 (2023)
Related entries: 7zl9, 7zly

Cited: 2 times
EuropePMC logo PMID: 36973264

Abstract

The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-Gi signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.

Articles citing this publication (2)

  1. Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2. Park JH, Kawakami K, Ishimoto N, Ikuta T, Ohki M, Ekimoto T, Ikeguchi M, Lee DS, Lee YH, Tame JRH, Inoue A, Park SY. Nat Commun 14 7150 (2023)
  2. Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2. Pan X, Ye F, Ning P, Zhang Z, Li X, Zhang B, Wang Q, Chen G, Gao W, Qiu C, Wu Z, Li J, Zhu L, Xia J, Gong K, Du Y. Cell Discov 9 118 (2023)


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