title: Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics.
abstract: The NMDA receptor family of glutamate receptor ion channels is formed by obligate heteromeric assemblies of GluN1, GluN2, and GluN3 subunits. GluN1 and GluN3 bind glycine, whereas GluN2 binds glutamate. Crystal structures of the GluN1 and GluN3A ligand-binding domains (LBDs) in their apo states unexpectedly reveal open- and closed-cleft conformations, respectively, with water molecules filling the binding pockets. Computed conformational free energy landscapes for GluN1, GluN2A, and GluN3A LBDs reveal that the apo-state LBDs sample closed-cleft conformations, suggesting that their agonists bind via a conformational selection mechanism. By contrast, free energy landscapes for the AMPA receptor GluA2 LBD suggest binding of glutamate via an induced-fit mechanism. Principal component analysis reveals a rich spectrum of hinge bending, rocking, twisting, and sweeping motions that are different for the GluN1, GluN2A, GluN3A, and GluA2 LBDs. This variation highlights the structural complexity of signaling by glutamate receptor ion channels.
authors: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, Department of Health and Human Services, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Yongneng
authors: Y
authors: Yao
authors: John
authors: J
authors: Belcher
authors: Anthony J
authors: AJ
authors: Berger
authors: Mark L
authors: ML
authors: Mayer
authors: Albert Y
authors: AY
authors: Lau
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008958:Models, Molecular; D025341:Principal Component Analysis; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D001059:Apoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016194:Receptors, N-Methyl-D-Aspartate; C096392:Grin3a protein, rat
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