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PDBsum entry 6hcc
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Membrane protein
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PDB id
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6hcc
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References listed in PDB file
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Key reference
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Title
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Crystal structures of potent dimeric positive allosteric modulators at the ligand-Binding domain of the glua2 receptor.
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Authors
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S.Laulumaa,
K.V.Hansen,
M.Masternak,
T.Drapier,
P.Francotte,
B.Pirotte,
K.Frydenvang,
J.S.Kastrup.
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Ref.
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ACS Med Chem Lett, 2019,
10,
243-247.
[DOI no: ]
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PubMed id
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Abstract
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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.
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