PDBsum entry 6hcc

Membrane protein

PDB id: 6hcc

Contents

Protein chains

264 a.a.

Ligands

FXW

GLU ×2

SO4 ×5

GOL ×7

PEG ×2

ACT ×4

Metals

_CL ×3

Waters ×681

PDB id:

6hcc

Name:

Membrane protein

Title:

Structure of glua2 ligand-binding domain (s1s2j-n775s) in complex with glutamate and tdpam02 at 1.6 a resolution.

Structure:

Glutamate receptor 2. Chain: a, b. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2,glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2,glutamate receptor ionotropic, ampa 2,glua2. Engineered: yes. Other_details: native glua2 is a membrane protein. The crystallized protein is a n775s-mutant of the glua2 ligand-binding domain. The

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: origami b.

Resolution:

1.62Å R-factor: 0.156 R-free: 0.182

Authors:

S.Laulumaa,K.V.Hansen,K.Frydenvang,J.S.Kastrup

Key ref:

S.Laulumaa et al. (2019). Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor. ACS Med Chem Lett, 10, 243-247. PubMed id: 30891120 DOI: 10.1021/acsmedchemlett.8b00369

Date:

14-Aug-18 Release date: 03-Apr-19

Protein chains

P19491  (GRIA2_RAT) -  Glutamate receptor 2 from Rattus norvegicus

Seq: 883 a.a.

Struc: 264 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1021/acsmedchemlett.8b00369

ACS Med Chem Lett 10:243-247 (2019)

PubMed id: 30891120

Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor.

S.Laulumaa, K.V.Hansen, M.Masternak, T.Drapier, P.Francotte, B.Pirotte, K.Frydenvang, J.S.Kastrup.

ABSTRACT

The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TDPAM02, with nanomolar potency at GluA2. Using X-ray crystallography, TDPAM01 and TDPAM02 were crystallized in the ligand-binding domain of the GluA2 flop isoform as well as in the flip-like mutant N775S and the preformed dimer L504Y-N775S. In all structures, one modulator molecule binds at the dimer interface with two characteristic hydrogen bonds being formed from the modulator to Pro515. Whereas the GluA2 dimers and modulator binding mode are similar when crystallized in the presence of l-glutamate, the shape of the binding site differs when no l-glutamate is present. TDPAM02 has no effect on domain closure in both apo and l-glutamate bound GluA2 dimers compared to structures without modulator.