Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators
| Autor: | Shuyan Yi, Sonya G. Lehto, Stefan I. McDonough, Klaus Michelsen, Erin F. DiMauro, Hao Chen, Maosheng Zhang, Stephen Schneider, Shawn Ayube, Jason A. Luther, Matthew H. Plant, Xin Huang, David J. Matson, Jeffrey R. Simard, Howard Bregman, Jacinthe Gingras, Paul L. Shaffer, Yohannes Teffera |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Protein Conformation alpha-Helical 0301 basic medicine Agonist medicine.drug_class Allosteric regulation Glycine Pharmacology Crystallography X-Ray Binding Competitive 03 medical and health sciences Receptors Glycine 0302 clinical medicine Allosteric Regulation Protein Domains Structural Biology medicine Humans Receptor Molecular Biology Glycine receptor Binding Sites Chemistry Hydrogen Bonding Long-term potentiation Potentiator Protein Subunits HEK293 Cells 030104 developmental biology Neuropathic pain 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature Structural & Molecular Biology. 24:108-113 |
| ISSN: | 1545-9985 1545-9993 |
| Popis: | Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain. |
| Databáze: | OpenAIRE |
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