title: Structural changes of regulatory domain heterodimer of N-methyl-D-aspartate receptor subunits GluN1 and GluN2B through the binding of spermine and ifenprodil.
abstract: Modeling the binding sites for spermine and ifenprodil on the regulatory (R) domains of the N-methyl-D-aspartate receptor GluN1 and GluN2B subunits was carried out after measuring spermine stimulation and ifenprodil inhibition at receptors containing GluN1 and GluN2B R domain mutants. Models were constructed based on the published crystal structure of the GluN1 and GluN2B R domains, which form a heterodimer (Nature 475:249-253, 2011). The experimental results and modeling suggest that a binding site for spermine was formed by the residues near the cleft between the R1 and R2 lobes of the GluN1 R domain (GluN1R) together with residues on the surface of the R2 (C-terminal side) lobe of the GluN2B R domain (GluN2BR). The ifenprodil binding site included residues on the surface of the R1 lobe (N-terminal side) of GluN1R together with residues near the cleft between the R1 and R2 lobes of GluN2BR. It was confirmed using a Western blot analysis that GluN1R and GluN2BR formed a heterodimer. Models of spermine and ifenprodil binding to the heterodimer were constructed. The modeling suggests that an open space between the two R1 lobes of GluN1R and GluN2BR is promoted through spermine binding and that the R1 lobes of GluN1R and GluN2BR approach each other through ifenprodil binding--an effect opposite to that seen with the binding of spermine.
authors: Faculty of Pharmacy, Chiba Institute of Science, Choshi, Chiba, Japan.
authors: Hideyuki
authors: H
authors: Tomitori
authors: Akiko
authors: A
authors: Suganami
authors: Ryotaro
authors: R
authors: Saiki
authors: Satomi
authors: S
authors: Mizuno
authors: Yuki
authors: Y
authors: Yoshizawa
authors: Takashi
authors: T
authors: Masuko
authors: Yutaka
authors: Y
authors: Tamura
authors: Kazuhiro
authors: K
authors: Nishimura
authors: Toshihiko
authors: T
authors: Toida
authors: Keith
authors: K
authors: Williams
authors: Keiko
authors: K
authors: Kashiwagi
authors: Kazuei
authors: K
authors: Igarashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013096:Spermine / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; C010739:ifenprodil