8IHI

Cryo-EM structure of HCA2-Gi complex with acifran

Summary for 8IHI

• Entry DOI: 10.2210/pdb8ihi/pdb
• EMDB information: 35445
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, scFv16, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 191734.14

Authors

Suzuki, S.,Nishikawa, K.,Suzuki, H.,Fujiyoshi, Y. (deposition date: 2023-02-22, release date: 2023-08-30, Last modification date: 2024-10-16)

Primary citation

Suzuki, S.,Tanaka, K.,Nishikawa, K.,Suzuki, H.,Oshima, A.,Fujiyoshi, Y.
Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding.
Nat Commun, 14:5899-5899, 2023

PubMed 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.

PubMed: 37736747
DOI: 10.1038/s41467-023-41650-7

Experimental method

ELECTRON MICROSCOPY (3.11 Å)