Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding

Shota Suzuki, Kotaro Tanaka, Kouki Nishikawa, Hiroshi Suzuki, Atsunori Oshima and Yoshinori Fujiyoshi ()
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Shota Suzuki: Tokyo Medical and Dental University Bunkyo-ku
Kotaro Tanaka: Nagoya University
Kouki Nishikawa: Tokyo University of Agriculture and Technology
Hiroshi Suzuki: Tokyo Medical and Dental University Bunkyo-ku
Atsunori Oshima: Nagoya University
Yoshinori Fujiyoshi: Tokyo Medical and Dental University Bunkyo-ku

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

Abstract: Abstract Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms.

Date: 2023
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DOI: 10.1038/s41467-023-41650-7

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