EMD-35463

Single-particle
3.28 Å
EMD-35463 Deposition: 24/02/2023
Map released: 03/01/2024
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-35463

Cryo-EM structure of human HCAR2-Gi complex without ligand (apo state)

EMD-35463

Single-particle
3.28 Å
EMD-35463 Deposition: 24/02/2023
Map released: 03/01/2024
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Cryo-EM structure of human HCAR2-Gi complex without ligand (apo state)
Fitted models: 8ij3 (Avg. Q-score: 0.506)

Deposition Authors: Pan X, Fang Y
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
(2023) Cell Discov , 9 , 118 - 118
PUBMED: 38012147
DOI: doi:10.1038/s41421-023-00610-7
ISSN: 2056-5968
Abstract:
Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.