9IK1
Cryo-EM structure of the human P2X3 receptor-compound 26a complex
This is a non-PDB format compatible entry.
Summary for 9IK1
| Entry DOI | 10.2210/pdb9ik1/pdb |
| EMDB information | 60647 |
| Descriptor | P2X purinoceptor 3, 4-[2-cyclopropyl-7-[[(1~{R})-1-naphthalen-2-ylethyl]amino]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxamide, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | p2x3 receptor, compound 26a, cryo-em, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 126075.52 |
| Authors | Kim, S.,Kim, G.R.,Kim, Y.O.,Han, X.,Nagel, J.,Kim, J.,Song, D.I.,Muller, C.E.,Yoon, M.H.,Jin, M.S.,Kim, Y.C. (deposition date: 2024-06-26, release date: 2024-09-04, Last modification date: 2025-07-02) |
| Primary citation | Kim, G.R.,Kim, S.,Kim, Y.O.,Han, X.,Nagel, J.,Kim, J.,Song, D.I.,Muller, C.E.,Yoon, M.H.,Jin, M.S.,Kim, Y.C. Discovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy. J.Med.Chem., 67:14443-14465, 2024 Cited by PubMed Abstract: The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist , featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of , thus presenting a novel, promising lead structure. PubMed: 39102524DOI: 10.1021/acs.jmedchem.4c01214 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.61 Å) |
Structure validation
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