EMD-44800

Single-particle
2.55 Å
EMD-44800 Deposition: 09/05/2024
Map released: 29/01/2025
Last modified: 29/01/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-44800

Cryo-EM structure of BAY-1797 bound to the full-length human P2X4 receptor in the closed state

EMD-44800

Single-particle
2.55 Å
EMD-44800 Deposition: 09/05/2024
Map released: 29/01/2025
Last modified: 29/01/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Membrane protein
Fitted models: 9bqi

Deposition Authors: Shi H , Ditter IA , Oken AC , Mansoor SE , Godsey MH, Mansoor SE
Human P2X4 receptor gating is modulated by a stable cytoplasmic cap and a unique allosteric pocket.
Shi H , Ditter IA , Oken AC , Mansoor SE
(2025) Sci Adv , 11 , eadr3315 - eadr3315
PUBMED: 39823330
DOI: doi:10.1126/sciadv.adr3315
ISSN: 2375-2548
Abstract:
P2X receptors (P2XRs) are adenosine 5'-triphosphate (ATP)-gated ion channels comprising homomeric and heteromeric trimers of seven subtypes (P2X1-P2X7) that confer different rates of desensitization. The helical recoil model of P2XR desensitization proposes stability of the cytoplasmic cap sets the rate of desensitization, but timing of its formation is unclear for slow-desensitizing P2XRs. We report cryo-electron microscopy structures of full-length wild-type human P2X4 receptor in apo closed, antagonist-bound inhibited, and ATP-bound desensitized states. Because the apo closed and antagonist-bound inhibited state structures of this slow-desensitizing P2XR include an intact cytoplasmic cap while the ATP-bound desensitized state structure does not, the cytoplasmic cap is formed before agonist binding. Furthermore, structural and functional data suggest the cytoplasmic cap is stabilized by lipids to modulate desensitization, and P2X4 is modified by glycosylation and palmitoylation. Last, our antagonist-bound inhibited state structure reveals features specific to the allosteric ligand-binding pocket in human receptors that facilitates development of small-molecule modulators.