Subtype- specific structural features of the hearing loss- associated human P2X2 receptor

• 成果类型: Article
• 署名作者: Westermann, Franka G.; Oken, Adam C.; Granith, Philip K. E.; Marimuthu, Parthiban; Mueller, Christa E.; Mansoor, Steven E.
• 署名单位: University of Bonn; University of Bonn; University of Bonn; Oregon Health & Science University; Abo Akademi University; Abo Akademi University; Oregon Health & Science University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9597
• DOI: 10.1073/pnas.2417753122
• 发表日期: 2025-09-16
• 关键词: gated ion channels; sound transduction; p2rx2 mutation; atp; expression; prediction; subunit; activation; molecules; proteins

摘要

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.