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PDBsum entry 6hpp
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Membrane protein
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PDB id
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6hpp
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References listed in PDB file
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Key reference
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Title
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Structural evidence for the binding of monocarboxylates and dicarboxylates at pharmacologically relevant extracellular sites of a pentameric ligand-Gated ion channel.
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Authors
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Z.Fourati,
L.Sauguet,
M.Delarue.
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Ref.
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Acta Crystallogr D Struct Biol, 2020,
76,
668-675.
[DOI no: ]
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PubMed id
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Abstract
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GLIC is a bacterial homologue of the pentameric ligand-gated ion channels
(pLGICs) that mediate the fast chemical neurotransmission of nerve signalling in
eukaryotes. Because the activation and allosteric modulation features are
conserved among prokaryotic and eukaryotic pLGICs, GLIC is commonly used as a
model to study the allosteric transition and structural pharmacology of pLGICs.
It has previously been shown that GLIC is inhibited by some carboxylic acid
derivatives. Here, experimental evidence for carboxylate binding to GLIC is
provided by solving its X-ray structures with a series of monocarboxylate and
dicarboxylate derivatives, and two carboxylate-binding sites are described: (i)
the `intersubunit' site that partially overlaps the canonical pLGIC orthosteric
site and (ii) the `intrasubunit' vestibular site, which is only occupied by a
subset of the described derivatives. While the intersubunit site is widely
conserved in all pLGICs, the intrasubunit site is only conserved in cationic
eukaryotic pLGICs. This study sheds light on the importance of these two
extracellular modulation sites as potential drug targets in pLGICs.
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