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

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.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Laulumaa S,Hansen KV,Masternak M,Drapier T,Francotte P,Pirotte B,Frydenvang K,Kastrup JS

doi

10.1021/acsmedchemlett.8b00369

subject

Has Abstract

pub_date

2018-11-04 00:00:00

pages

243-247

issue

3

issn

1948-5875

journal_volume

10

pub_type

杂志文章

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