Figure 5.
Figure 5. Crystal structures of NMDA receptor ABDs. (A) Structures of the soluble GluN1/2 ABD heterodimers reveal the subunit interface and back-to-back dimer arrangement of the ABDs. The structure shown here is for the GluN1/2A ABD heterodimer with bound glutamate and glycine shown as spheres (Protein Data Bank accession no. 5I57; Yi et al., 2016). The top view of the structure highlights sites I–III at the subunit interface. (B) Overlay of crystal structures of GluN1/2A ABD heterodimers in complex with glycine and either glutamate agonist (Protein Data Bank accession no. 5I57; Yi et al., 2016) or a competitive glutamate site antagonist (Protein Data Bank accession no. 5U8C; Romero-Hernandez and Furukawa, 2017). Activation of NMDA receptors requires agonist-induced ABD closure. Competitive antagonists bind the ABD without inducing domain closure, thereby preventing receptor activation. (C) Magnified views of the glutamate-binding site with bound GluN2A-preferring antagonists NVP-AAM077 (Protein Data Bank accession no. 5U8C; Romero-Hernandez and Furukawa, 2017) or ST3 (Protein Data Bank accession no. 5VII; Lind et al., 2017). Schild analyses demonstrated that NVP-AAM077 has 11-fold and ST3 has 15-fold preference for GluN1/2A over GluN1/2B receptors (data adapted from Lind et al., 2017). The crystal structures reveal a binding mode in which NVP-AAM077 and ST3 occupy a cavity that extends toward GluN1 at the subunit interface, and mutational analyses show that the GluN2A preference of these antagonists is primarily mediated by four nonconserved residues (Lys738, Tyr754, Ile755, and Thr758) that do not directly contact the ligand but are positioned within 12 Å of the glutamate-binding site. (D) Structure of the agonist-bound GluN1/2A ABD heterodimer with the NAM MPX-007 bound at site II in the subunit interface (Protein Data Bank accession no. 5I59; Yi et al., 2016). (E) Magnified views of site II in GluN1/2A ABD heterodimer with bound MPX-007 (NAM; Protein Data Bank accession no. 5I59; Yi et al., 2016) or PAM GNE-8324 (Protein Data Bank accession no. 5H8Q; Hackos et al., 2016). The overlay illustrates the distinct effects of NAM and PAM binding on Val783 in GluN2A and Tyr535 in GluN1. The GluN2A selectivity of the NAMs and PAMs binding at this modulatory site is mediated by Val783 in GluN2A, which is nonconserved among GluN2 subunits (Phe in GluN2B and Leu in GluN2C/GluN2D).

Crystal structures of NMDA receptor ABDs. (A) Structures of the soluble GluN1/2 ABD heterodimers reveal the subunit interface and back-to-back dimer arrangement of the ABDs. The structure shown here is for the GluN1/2A ABD heterodimer with bound glutamate and glycine shown as spheres (Protein Data Bank accession no. 5I57; Yi et al., 2016). The top view of the structure highlights sites I–III at the subunit interface. (B) Overlay of crystal structures of GluN1/2A ABD heterodimers in complex with glycine and either glutamate agonist (Protein Data Bank accession no. 5I57; Yi et al., 2016) or a competitive glutamate site antagonist (Protein Data Bank accession no. 5U8C; Romero-Hernandez and Furukawa, 2017). Activation of NMDA receptors requires agonist-induced ABD closure. Competitive antagonists bind the ABD without inducing domain closure, thereby preventing receptor activation. (C) Magnified views of the glutamate-binding site with bound GluN2A-preferring antagonists NVP-AAM077 (Protein Data Bank accession no. 5U8C; Romero-Hernandez and Furukawa, 2017) or ST3 (Protein Data Bank accession no. 5VII; Lind et al., 2017). Schild analyses demonstrated that NVP-AAM077 has 11-fold and ST3 has 15-fold preference for GluN1/2A over GluN1/2B receptors (data adapted from Lind et al., 2017). The crystal structures reveal a binding mode in which NVP-AAM077 and ST3 occupy a cavity that extends toward GluN1 at the subunit interface, and mutational analyses show that the GluN2A preference of these antagonists is primarily mediated by four nonconserved residues (Lys738, Tyr754, Ile755, and Thr758) that do not directly contact the ligand but are positioned within 12 Å of the glutamate-binding site. (D) Structure of the agonist-bound GluN1/2A ABD heterodimer with the NAM MPX-007 bound at site II in the subunit interface (Protein Data Bank accession no. 5I59; Yi et al., 2016). (E) Magnified views of site II in GluN1/2A ABD heterodimer with bound MPX-007 (NAM; Protein Data Bank accession no. 5I59; Yi et al., 2016) or PAM GNE-8324 (Protein Data Bank accession no. 5H8Q; Hackos et al., 2016). The overlay illustrates the distinct effects of NAM and PAM binding on Val783 in GluN2A and Tyr535 in GluN1. The GluN2A selectivity of the NAMs and PAMs binding at this modulatory site is mediated by Val783 in GluN2A, which is nonconserved among GluN2 subunits (Phe in GluN2B and Leu in GluN2C/GluN2D).

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