5I58

GLUTAMATE- AND GLYCINE-BOUND GLUN1/GLUN2A AGONIST BINDING DOMAINS WITH MPX-004


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.52 Å
  • R-Value Free: 0.292 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors.

Yi, F.Mou, T.C.Dorsett, K.N.Volkmann, R.A.Menniti, F.S.Sprang, S.R.Hansen, K.B.

(2016) Neuron 91: 1316-1329

  • DOI: https://doi.org/10.1016/j.neuron.2016.08.014
  • Primary Citation of Related Structures:  
    5I56, 5I57, 5I58, 5I59, 5JTY

  • PubMed Abstract: 

    NMDA receptors mediate excitatory synaptic transmission and regulate synaptic plasticity in the central nervous system, but their dysregulation is also implicated in numerous brain disorders. Here, we describe GluN2A-selective negative allosteric modulators (NAMs) that inhibit NMDA receptors by stabilizing the apo state of the GluN1 ligand-binding domain (LBD), which is incapable of triggering channel gating. We describe structural determinants of NAM binding in crystal structures of the GluN1/2A LBD heterodimer, and analyses of NAM-bound LBD structures corresponding to active and inhibited receptor states reveal a molecular switch in the modulatory binding site that mediate the allosteric inhibition. NAM binding causes displacement of a valine in GluN2A and the resulting steric effects can be mitigated by the transition from glycine bound to apo state of the GluN1 LBD. This work provides mechanistic insight to allosteric NMDA receptor inhibition, thereby facilitating the development of novel classes NMDA receptor modulators as therapeutic agents.


  • Organizational Affiliation

    Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor ionotropic, NMDA 1,Glutamate receptor ionotropic, NMDA 1292Rattus norvegicusMutation(s): 0 
Gene Names: Grin1Nmdar1
UniProt
Find proteins for P35439 (Rattus norvegicus)
Explore P35439 
Go to UniProtKB:  P35439
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35439
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor ionotropic, NMDA 2A,Glutamate receptor ionotropic, NMDA 2A281Rattus norvegicusMutation(s): 0 
Gene Names: Grin2a
UniProt
Find proteins for Q00959 (Rattus norvegicus)
Explore Q00959 
Go to UniProtKB:  Q00959
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00959
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
67R
Query on 67R

Download Ideal Coordinates CCD File 
E [auth B]5-({[(3-chloro-4-fluorophenyl)sulfonyl]amino}methyl)-N-[(2-methyl-1,3-thiazol-5-yl)methyl]pyrazine-2-carboxamide
C17 H15 Cl F N5 O3 S2
BRNKHERDLJYUNK-UHFFFAOYSA-N
GLU
Query on GLU

Download Ideal Coordinates CCD File 
D [auth B]GLUTAMIC ACID
C5 H9 N O4
WHUUTDBJXJRKMK-VKHMYHEASA-N
GLY
Query on GLY

Download Ideal Coordinates CCD File 
C [auth A]GLYCINE
C2 H5 N O2
DHMQDGOQFOQNFH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
67R BindingDB:  5I58 IC50: 61 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.52 Å
  • R-Value Free: 0.292 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.239 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.919α = 90
b = 86.425β = 90
c = 122.628γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesP20GM103546

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-21
    Type: Initial release
  • Version 1.1: 2016-10-05
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description