9YDV

MRS2905 bound P2Y14 Receptor in complex with Gi

This is a non-PDB format compatible entry.

Summary for 9YDV

• Entry DOI: 10.2210/pdb9ydv/pdb
• EMDB information: 72836
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, 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: gpcr, p2y receptor, purinergic, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 151727.24

Authors

Fay, J.F. (deposition date: 2025-09-23, release date: 2025-11-19, Last modification date: 2026-01-07)

Primary citation

Fay, J.F.,Kousouros, J.,Gao, Z.G.,Pavan, M.,Oliva, P.,Pramanik, A.,Meyer, C.,Kurma, S.H.,Xu, W.,Krumm, B.,Jacobson, K.A.
UDP-glucose and MRS2905 agonist-bound states of the purinergic P2Y 14 receptor.
Commun Biol, 8:1816-1816, 2025

PubMed Abstract: P2Y receptors respond to uracil-diphosphate-hexose conjugates, yet how this receptor selectively recognizes both uracil-nucleotides and hexose moieties of diverse agonists remains unclear. Here we report the active agonist-bound G protein-bound states of the P2Y G protein-coupled receptor (GPCR) bound to endogenous agonist uridine diphosphate glucose (UDP-glucose) and 2-thiouridine-5'-O-(α,β-methylene)diphosphate (MRS2905). The cryo-EM structures of the heterotrimeric complexes with 3.19 Å and 3.05 Å global resolution, respectively, with local refinements reaching 2.87 Å and 3.22 Å for the masked receptor region. Our structures reveal a pronounced extracellular facing electronegative vestibule connecting to a smaller nucleotide binding subpocket (~300Å volume) that is shielded by extracellular loop 2 (ECL2). A glucose-binding subpocket is spatially delimited by residue V93; mutation to Trp selectively blocks UDP-glucose while permitting MRS2905 and antagonist binding. These findings provide atomic insights into uracil recognition, reveal how the receptor accommodates diverse flexible UDP-sugars, and promise to enable rational drug discovery of therapeutic P2YR modulators.

PubMed: 41272298
DOI: 10.1038/s42003-025-09174-6

Experimental method

ELECTRON MICROSCOPY (3.05 Å)