Structural Basis of Functional Transitions in Mammalian NMDA Receptors

• Published in: Cell 2020-07, Vol.182 (2), p.357-371.e13
• Main Authors: Chou, Tsung-Han, Tajima, Nami, Romero-Hernandez, Annabel, Furukawa, Hiro
• Format: Article
• Language: English
• Subjects: BASIC BIOLOGICAL SCIENCES; Binding Sites; Binding, Competitive; channel activation and inhibition mechanisms; cryo-EM; Cryoelectron Microscopy; Crystallography, X-Ray; Dimerization; electron cryo-microscopy; Glutamic Acid - chemistry; Glutamic Acid - metabolism; Glycine - chemistry; Glycine - metabolism; Humans; ligand-gated ion channels; Ligands; Molecular Dynamics Simulation; N-methyl-D-aspartate receptors; NMDAR antagonists; NMDARs; Protein Structure, Quaternary; Protein Subunits - agonists; Protein Subunits - antagonists & inhibitors; Protein Subunits - genetics; Protein Subunits - metabolism; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; X-ray crystallography
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.05.052

Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology. [Display omitted] •Structures of GluN1b-GluN2B NMDARs in distinct states were solved at 4 Å or better•Agonist-binding “stretches” the GluN2B LBD-TMD linkers to perturb the channel gate•A GluN2 antagonist mediates inhibition by relaxing the GluN2 LBD-TMD linkers•A GluN1 antagonist reorients GluN1-GluN2 dimers to relax the GluN2 LBD-TMD linkers Multiple structures in distinct ligand states provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology.