6HCB

STRUCTURE OF GLUA2 LIGAND-BINDING DOMAIN (S1S2J-N775S) IN COMPLEX WITH GLUTAMATE AND TDPAM01 AT 1.9 A RESOLUTION.

6HCB の概要

• エントリーDOI: 10.2210/pdb6hcb/pdb
• 分子名称: Glutamate receptor 2, SULFATE ION, GLUTAMIC ACID, ... (8 entities in total)
• 機能のキーワード: ampa receptor, glua2, ligand-binding domain, glua2-s1s2j-n775s, membrane protein, signaling protein, positive allosteric modulator
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60807.19

構造登録者

Laulumaa, S.,Masternak, M.,Frydenvang, K.,Kastrup, J.S. (登録日: 2018-08-14, 公開日: 2019-04-03, 最終更新日: 2024-11-13)

主引用文献

Laulumaa, S.,Hansen, K.V.,Masternak, M.,Drapier, T.,Francotte, P.,Pirotte, B.,Frydenvang, K.,Kastrup, J.S.
Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor.
Acs Med.Chem.Lett., 10:243-247, 2019

PubMed 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.

PubMed: 30891120
DOI: 10.1021/acsmedchemlett.8b00369

実験手法

X-RAY DIFFRACTION (1.9 Å)