PDBsum entry 3ilt

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protein ligands metals Protein-protein interface(s) links
Signaling protein PDB id
Protein chains
258 a.a. *
GLU ×3
TRU ×3
_ZN ×5
Waters ×153
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of the ampa subunit glur2 bound to the all modulator, trichlormethiazide
Structure: Glutamate receptor 2. Chain: b, e, h. Fragment: s1s2 binding domain. Synonym: glur-2, glur-b, glur-k2, glutamate receptor ionotr 2, ampa-selective glutamate receptor 2. Engineered: yes. Mutation: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: glur2, gria2, gria2. Glur2. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.11Å     R-factor:   0.212     R-free:   0.261
Authors: A.H.Ahmed,C.P.Ptak,R.E.Oswald
Key ref: C.P.Ptak et al. (2009). Probing the allosteric modulator binding site of GluR2 with thiazide derivatives. Biochemistry, 48, 8594-8602. PubMed id: 19673491
07-Aug-09     Release date:   15-Sep-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P19491  (GRIA2_RAT) -  Glutamate receptor 2
883 a.a.
258 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     transport   1 term 
  Biochemical function     transporter activity     3 terms  


Biochemistry 48:8594-8602 (2009)
PubMed id: 19673491  
Probing the allosteric modulator binding site of GluR2 with thiazide derivatives.
C.P.Ptak, A.H.Ahmed, R.E.Oswald.
Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission and are therapeutic targets for cognitive enhancement and treatment of schizophrenia. The binding domains of these tetrameric receptors consist of two dimers, and the dissociation of the dimer interface of the ligand-binding domain leads to desensitization in the continued presence of agonist. Positive allosteric modulators act by strengthening the dimer interface and reducing the level of desensitization, thereby increasing steady-state activation. Removing the desensitized state for simplified analysis of receptor activation is commonly achieved using cyclothiazide (CTZ), the most potent modulator of the benzothiadiazide class, with the flip form of the AMPA receptor subtype. IDRA-21, the first benzothiadiazide to have an effect in behavioral tests, is an important lead compound in clinical trials for cognitive enhancement as it can cross the blood-brain barrier. Intermediate structures between CTZ and IDRA-21 show reduced potency, suggesting that these two compounds have different contact points associated with binding. To understand how benzothiadiazides bind to the pocket bridging the dimer interface, we generated a series of crystal structures of the GluR2 ligand-binding domain complexed with benzothiadiazide derivatives (IDRA-21, hydroflumethiazide, hydrochlorothiazide, chlorothiazide, trichlormethiazide, and althiazide) for comparison with an existing structure for cyclothiazide. The structures detail how changes in the substituents at the 3- and 7-positions of the hydrobenzothiadiazide ring shift the orientation of the drug in the binding site and, in some cases, change the stoichiometry of binding. All derivatives maintain a hydrogen bond with the Ser754 hydroxyl, affirming the partial selectivity of the benzothiadiazides for the flip form of AMPA receptors.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20713069 J.Pøhlsgaard, K.Frydenvang, U.Madsen, and J.S.Kastrup (2011).
Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators.
  Neuropharmacology, 60, 135-150.  
21349697 M.L.Mayer (2011).
Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation.
  Curr Opin Neurobiol, 21, 283-290.  
20199107 A.H.Ahmed, C.P.Ptak, and R.E.Oswald (2010).
Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA.
  Biochemistry, 49, 2843-2850.
PDB codes: 3m3f 3m3k 3m3l
20163115 A.H.Ahmed, and R.E.Oswald (2010).
Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.
  J Med Chem, 53, 2197-2203.
PDB codes: 3lsf 3lsl 3lsw 3lsx
20839295 C.J.Illingworth, P.D.Scott, K.E.Parkes, C.R.Snell, M.P.Campbell, and C.A.Reynolds (2010).
Connectivity and binding-site recognition: applications relevant to drug design.
  J Comput Chem, 31, 2677-2688.  
20423333 S.E.Ward, B.D.Bax, and M.Harries (2010).
Challenges for and current status of research into positive modulators of AMPA receptors.
  Br J Pharmacol, 160, 181-190.  
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