8QEZ

Crystal structure of the AMPA receptor GluA2-L504Y-N775S ligand binding domain in complex with L-glutamate and positive allosteric modulator BPAM395 at 1.55A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 

Starting Model: experimental
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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted UF5Click on this verticalbar to view detailsBest fitted GLUClick on this verticalbar to view details

This is version 1.1 of the entry. See complete history


Literature

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators.

Francotte, P.Bay, Y.Goffin, E.Colson, T.Lesenfants, C.Dorosz, J.Laulumaa, S.Fraikin, P.de Tullio, P.Beaufour, C.Botez, I.Pickering, D.S.Frydenvang, K.Danober, L.Kristensen, A.S.Kastrup, J.S.Pirotte, B.

(2023) Eur J Med Chem 264: 116036-116036

  • DOI: https://doi.org/10.1016/j.ejmech.2023.116036
  • Primary Citation of Related Structures:  
    8QEZ

  • PubMed Abstract: 

    The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.


  • Organizational Affiliation

    Center for Interdisciplinary Research on Medicines (CIRM) - Laboratory of Medicinal Chemistry, University of Liège, Avenue Hippocrate 15 (B36), B-4000, Liège, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor 2
A, B, C
264Rattus norvegicusMutation(s): 2 
Gene Names: Gria2Glur2
Membrane Entity: Yes 
UniProt
Find proteins for P19491 (Rattus norvegicus)
Explore P19491 
Go to UniProtKB:  P19491
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP19491
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UF5 (Subject of Investigation/LOI)
Query on UF5

Download Ideal Coordinates CCD File 
EA [auth C],
M [auth A],
U [auth B]
6-chloranyl-4-cyclopropyl-2,3-dihydrothieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide
C8 H9 Cl N2 O2 S2
PJOUJJTUKBFKPV-UHFFFAOYSA-N
GLU (Subject of Investigation/LOI)
Query on GLU

Download Ideal Coordinates CCD File 
D [auth A],
O [auth B],
W [auth C]
GLUTAMIC ACID
C5 H9 N O4
WHUUTDBJXJRKMK-VKHMYHEASA-N
CAC
Query on CAC

Download Ideal Coordinates CCD File 
Z [auth C]CACODYLATE ION
C2 H6 As O2
OGGXGZAMXPVRFZ-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
BA [auth C],
CA [auth C],
DA [auth C],
T [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
P [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
AA [auth C]
I [auth A]
J [auth A]
K [auth A]
L [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
FA [auth C],
N [auth A],
V [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.316α = 90
b = 163.416β = 90
c = 47.466γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALAdata scaling
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted UF5Click on this verticalbar to view detailsBest fitted GLUClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2023-12-27
    Type: Initial release
  • Version 1.1: 2024-10-16
    Changes: Structure summary