Insights into the Activation Mechanism of HCA1, HCA2, and HCA3 DOI Creative Commons
Jiening Wang, Yuxia Qian, Zhen Han

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on its clinical application has been limited adverse effects. Therefore, role HCA1 as a promising target for treatment lipolysis warrants further exploration. As HCAs exhibit high similarity when with diverse selective agonists, conserved yet unique activation mechanism remains undisclosed. Herein, we unveil cryo-electron microscopy structures 3,5-DHBA-HCA1-Gi signaling complex, acifran- MK6892-bound HCA2-Gi complexes, acifran-HCA3-Gi complex. Comparative analysis across reveals key residues in contributing to stabilization ligand-binding pocket. Furthermore, chimeric complexes mutational analyses identify that are pivotal HCA2 selectivity. Our findings elucidate critical structural insights into mechanisms ligand recognition within broaden our comprehension specificity binding HCA family.

Language: Английский

Insights into the Activation Mechanism of HCA1, HCA2, and HCA3 DOI Creative Commons
Jiening Wang, Yuxia Qian, Zhen Han

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on its clinical application has been limited adverse effects. Therefore, role HCA1 as a promising target for treatment lipolysis warrants further exploration. As HCAs exhibit high similarity when with diverse selective agonists, conserved yet unique activation mechanism remains undisclosed. Herein, we unveil cryo-electron microscopy structures 3,5-DHBA-HCA1-Gi signaling complex, acifran- MK6892-bound HCA2-Gi complexes, acifran-HCA3-Gi complex. Comparative analysis across reveals key residues in contributing to stabilization ligand-binding pocket. Furthermore, chimeric complexes mutational analyses identify that are pivotal HCA2 selectivity. Our findings elucidate critical structural insights into mechanisms ligand recognition within broaden our comprehension specificity binding HCA family.

Language: Английский

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