title: Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators.
abstract: 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.
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Shaffer
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Ayube
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.affiliation: Department of Protein Technologies, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Luther
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Matson
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Stefan I
authors.initials: SI
authors.lastname: McDonough
authors.affiliation: Department of Discovery Attribute Sciences, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.affiliation: Department of Discovery Attribute Sciences, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Plant
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.affiliation: Department of Pharmacokinetics &Drug Metabolism, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Neuroscience, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Gingras
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D021122:Protein Subunits / Q000737:chemistry; D018009:Receptors, Glycine / Q000737:chemistry*
chemical_list: D021122:Protein Subunits; D018009:Receptors, Glycine; C113965:glycine receptor alpha3 subunit; D005998:Glycine