| Autor: |
Oken AC; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA., Ditter IA; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA., Lisi NE; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA., Krishnamurthy I; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA., Godsey MH; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA., Mansoor SE; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.; Division of Cardiovascular Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA. |
| Abstrakt: |
P2X receptors are trimeric ion channels activated by adenosine triphosphate (ATP) that contribute to pathophysiological processes ranging from asthma to neuropathic pain and neurodegeneration. A number of small-molecule antagonists have been identified for these important pharmaceutical targets. However, the molecular pharmacology of P2X receptors is poorly understood because of the chemically disparate nature of antagonists and their differential actions on the seven constituent subtypes. Here, we report high-resolution cryo-electron microscopy structures of the homomeric rat P2X 7 receptor bound to five previously known small-molecule allosteric antagonists and a sixth antagonist that we identify. Our structural, biophysical, and electrophysiological data define the molecular determinants of allosteric antagonism in this pharmacologically relevant receptor, revealing three distinct classes of antagonists that we call shallow, deep, and starfish. Starfish binders, exemplified by the previously unidentified antagonist methyl blue, represent a unique class of inhibitors with distinct functional properties that could be exploited to develop potent P2X 7 ligands with substantial clinical impact. |
