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TitleUDP-glucose and MRS2905 agonist-bound states of the purinergic P2Y receptor.
Journal, issue, pagesCommun Biol, Vol. 8, Issue 1, Page 1816, Year 2025
Publish dateNov 21, 2025
AuthorsJonathan F Fay / Joseph Kousouros / Zhan-Guo Gao / Matteo Pavan / Paola Oliva / Asmita Pramanik / Clayton Meyer / Siva Hariprasad Kurma / Wen Xu / Brian Krumm / Kenneth A Jacobson /
PubMed AbstractP2Y 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 ...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.
External linksCommun Biol / PubMed:41272298 / PubMed Central
MethodsEM (single particle)
Resolution2.87 - 3.22 Å
Structure data

72835

9ydu

EMDB-72835, PDB-9ydu:
UDPG bound P2Y14 Receptor in complex with Gi
Method: EM (single particle) / Resolution: 3.19 Å

72836

9ydv

EMDB-72836, PDB-9ydv:
MRS2905 bound P2Y14 Receptor in complex with Gi
Method: EM (single particle) / Resolution: 3.05 Å

EMDB-72837: P2Y14R bound to MRS2905 (local refinement)
Method: EM (single particle) / Resolution: 3.22 Å

EMDB-72838: P2Y14R bound to UDPG (local refinement)
Method: EM (single particle) / Resolution: 2.87 Å

Chemicals

ChemComp-UPG:
URIDINE-5'-DIPHOSPHATE-GLUCOSE

PDB-1cvs:
CRYSTAL STRUCTURE OF A DIMERIC FGF2-FGFR1 COMPLEX

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / P2Y Receptor / purinergic

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