6Q60

Structure of GluA2 ligand-binding domain (S1S2J) in complex with the agonist (S)-2-Amino-3-(2-methyl-5-hydroxy-2H-1,2,3-triazol-4-yl)propanoic acid at 1.55 A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.175 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.149 

wwPDB Validation 3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.

Sainas, S.Temperini, P.Farnsworth, J.C.Yi, F.Mollerud, S.Jensen, A.A.Nielsen, B.Passoni, A.Kastrup, J.S.Hansen, K.B.Boschi, D.Pickering, D.S.Clausen, R.P.Lolli, M.L.

(2019) J Med Chem 62: 4467-4482

  • DOI: 10.1021/acs.jmedchem.8b01986
  • Structures With Same Primary Citation

  • PubMed Abstract: 
  • We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazol ...

    We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtypes, confirmed also by an unusual binding mode observed for the crystal structures in complex with the AMPA receptor GluA2 agonist-binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist-binding sites of the N-methyl-d-aspartic acid receptor. These observations demonstrate novel features that arise when employing a hydroxytriazole moiety as a bioisostere for the distal carboxylic acid in glutamate receptor agonists.


    Organizational Affiliation

    Department of Drug Science and Technology , University of Turin , via P.Giuria 9 , 10125 Turin , Italy.



Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Glutamate receptor 2
A, B
264Rattus norvegicusMutation(s): 0 
Gene Names: Gria2Glur2
Find proteins for P19491 (Rattus norvegicus)
Go to UniProtKB:  P19491
Small Molecules
Ligands 5 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
HJH
Query on HJH

Download CCD File 
A, B
(2~{S})-2-azanyl-3-(2-methyl-5-oxidanyl-1,2,3-triazol-4-yl)propanoic acid
C6 H10 N4 O3
INIGHNGDJJNUCU-VKHMYHEASA-N
 Ligand Interaction
SO4
Query on SO4

Download CCD File 
A, B
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
 Ligand Interaction
GOL
Query on GOL

Download CCD File 
A, B
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
 Ligand Interaction
CL
Query on CL

Download CCD File 
A, B
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
 Ligand Interaction
LI
Query on LI

Download CCD File 
A, B
LITHIUM ION
Li
HBBGRARXTFLTSG-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.175 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.149 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.344α = 90
b = 122.254β = 90
c = 47.351γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2019-04-17
    Type: Initial release
  • Version 1.1: 2019-05-22
    Changes: Data collection, Database references