2. Academic Validation
  3. UDP-glucose and MRS2905 agonist-bound states of the purinergic P2Y14 receptor

UDP-glucose and MRS2905 agonist-bound states of the purinergic P2Y14 receptor

  • Commun Biol. 2025 Nov 21;8(1):1816. doi: 10.1038/s42003-025-09174-6.
Jonathan F Fay 1,  Joseph Kousouros 2,  Zhan-Guo Gao 3,  Matteo Pavan 3,  Paola Oliva 3,  Asmita Pramanik 3,  Clayton Meyer 3,  Siva Hariprasad Kurma 3,  Wen Xu 2,  Brian Krumm 4,  Kenneth A Jacobson 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, USA. [email protected].
  • 2 Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, USA.
  • 3 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 4 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 5 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
PMID: 41272298 DOI: 10.1038/s42003-025-09174-6
Abstract

P2Y14 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 P2Y14 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 (~300Å3 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 P2Y14R modulators.

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