9VMO

Cryo-EM structure of the ITA-OXGR1-Gq complex

Summary for 9VMO

• Entry DOI: 10.2210/pdb9vmo/pdb
• EMDB information: 65193
• Descriptor: Guanine nucleotide-binding protein G(q) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: oxgr1, gq, ita, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 144269.51

Authors

Tang, X.J.,Sun, J.P.,Guo, L.L.,Li, J.,Deng, Z.L.,Xiao, W.Q.,Zhu, Y.,Zhu, K.K. (deposition date: 2025-06-28, release date: 2026-03-18)

Primary citation

Xiao, W.,Zhu, Y.,Tang, X.,Zhu, K.,Zhang, W.,Chen, M.,Cai, K.,Xu, S.,Wu, Z.,Wang, M.,Liu, J.,Long, L.,Tan, Z.,Wu, A.,Zhou, S.,Zhao, Z.,Tang, Y.,Huang, Y.,Wang, B.,Liu, F.,Wang, Q.,Yang, F.,Jian, D.,Shi, W.,Xie, H.,Chen, X.,Guo, L.,Deng, Z.,Sun, J.,Li, J.
Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema.
Cell, 2026

PubMed Abstract: Rosacea, an inflammatory skin disorder, poses a dilemma owing to limited effectiveness of treatments for pathological vasodilation-mediated erythema. Here, we identify oxoglutaric acid (α-KG) as a rosacea-associated metabolite elevated in patients and correlated with erythema severity. Exogenous α-KG administration ameliorates rosacea-like manifestations in murine models. Mechanistically, α-KG activates OXGR1, a vascular smooth muscle cell (VSMC)-enriched G protein-coupled receptor (GPCR) to induce Gq signaling and enhance MYL9 phosphorylation, promoting VSMC contraction and limiting vasodilation. Cryo-electron microscopy (cryo-EM) structures of OXGR1-Gq complexes bound to α-KG or itaconate reveal a specific bipartite-acid pocket recognizing its endogenous agonist and an activation mechanism distinct from classical GPCRs. Building on these structures, we developed A-1, a synthetic selective OXGR1 agonist that mitigates erythema and inflammation with efficacy comparable to first-line therapy while offering enhanced safety in rosacea-like models. These findings link a metabolite to vascular dysfunction and nominate OXGR1 agonism for precision treatment of erythema and vascular disorders.

PubMed: 41791372
DOI: 10.1016/j.cell.2026.01.036

Experimental method

ELECTRON MICROSCOPY (2.4 Å)