5M2V

Structure of GluK1 ligand-binding domain (S1S2) in complex with (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid at 3.18 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.18 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.

Krogsgaard-Larsen, N.Delgar, C.G.Koch, K.Brown, P.M.Moller, C.Han, L.Huynh, T.H.Hansen, S.W.Nielsen, B.Bowie, D.Pickering, D.S.Kastrup, J.S.Frydenvang, K.Bunch, L.

(2017) J Med Chem 60: 441-457

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01516
  • Primary Citation of Related Structures:  
    5M2V

  • PubMed Abstract: 

    Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K i = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC 50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.


  • Organizational Affiliation

    Bowie Lab, Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University , Montreal, Quebec H3G 0B1, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor ionotropic, kainate 1,Glutamate receptor ionotropic, kainate 1
A, B
257Rattus norvegicusMutation(s): 0 
Gene Names: Grik1Glur5
UniProt
Find proteins for P22756 (Rattus norvegicus)
Explore P22756 
Go to UniProtKB:  P22756
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22756
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7E5
Query on 7E5

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(2~{S},4~{R})-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid
C12 H13 N O5
XHABYXGKUZQAIW-APPZFPTMSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
I [auth B]
J [auth B]
D [auth A],
E [auth A],
F [auth A],
I [auth B],
J [auth B],
K [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
L [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.18 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.986α = 90
b = 71.986β = 90
c = 233.363γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-01-11
    Type: Initial release
  • Version 1.1: 2017-01-25
    Changes: Database references
  • Version 1.2: 2017-08-09
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description