9DDV

Cryo-EM structure of the human P2X2 receptor in the apo closed state

This is a non-PDB format compatible entry.

Summary for 9DDV

• Entry DOI: 10.2210/pdb9ddv/pdb
• EMDB information: 46781
• Descriptor: P2X purinoceptor 2, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: membrane protein, ion channel, ligand-gated ion channel, p2x receptor, p2xr
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 156772.24

Authors

Westermann, F.G.,Oken, A.C.,Muller, C.E.,Mansoor, S.E. (deposition date: 2024-08-28, release date: 2025-09-24)

Primary citation

Westermann, F.G.,Oken, A.C.,Granith, P.K.E.,Marimuthu, P.,Muller, C.E.,Mansoor, S.E.
Subtype-specific structural features of the hearing loss-associated human P2X2 receptor.
Proc.Natl.Acad.Sci.USA, 122:e2417753122-e2417753122, 2025

PubMed Abstract: The P2X2 receptor (P2X2R) is a slowly desensitizing adenosine triphosphate (ATP)-gated ion channel that is highly expressed in the cochlea. When mutated, the P2X2R exacerbates age- and noise-related hearing loss, but selective modulators of the receptor are lacking, and the molecular basis of activation and desensitization remains poorly understood. Here, we determine high-resolution cryoelectron microscopy structures of the full-length wild-type human P2X2R in an apo closed state and two distinct ATP-bound desensitized states. In the apo closed state structure, we observe features unique to the P2X2R and locate disease mutations within or near the transmembrane domain. In addition, our ATP-bound structures show how free anionic ATP forms subtype-specific interactions with the orthosteric binding site. We identify and characterize two different ATP-bound desensitized state structures, one similar to published models for other P2XR subtypes, and a second alternate conformation not previously observed. A loop adjacent to the orthosteric binding site between these two ATP-bound desensitized state structures undergoes significant conformational changes. These movements are supported by multireplicate, microsecond-scale molecular dynamics simulation studies and suggest a path by which ATP could enter or leave the orthosteric pocket. Together, our results provide structural insights into the P2X2R, facilitating structure-based drug development for this therapeutically important target.

PubMed: 40938707
DOI: 10.1073/pnas.2417753122

Experimental method

ELECTRON MICROSCOPY (2.71 Å)