Nature structural & molecular biology, 2017-02, Vol.24 (2), p.108-113
2017
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- Autor(en) / Beteiligte
- Titel
- Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators
- Ist Teil von
- Nature structural & molecular biology, 2017-02, Vol.24 (2), p.108-113
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1545-9993eISSN: 1545-9985DOI: 10.1038/nsmb.3329Titel-ID: cdi_pubmed_primary_27991902
- Format
- –
- Schlagworte
- Allosteric Regulation, Binding Sites, Binding, Competitive, Crystallography, X-Ray, Glycine - chemistry, HEK293 Cells, Humans, Hydrogen Bonding, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Domains, Protein Subunits - chemistry, Receptors, Glycine - chemistry