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PDBsum entry 5afm
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Transport protein
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PDB id
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5afm
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References listed in PDB file
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Key reference
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Title
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Molecular blueprint of allosteric binding sites in a homologue of the agonist-Binding domain of the α7 nicotinic acetylcholine receptor.
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Authors
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R.Spurny,
S.Debaveye,
A.Farinha,
K.Veys,
A.M.Vos,
T.Gossas,
J.Atack,
S.Bertrand,
D.Bertrand,
U.H.Danielson,
G.Tresadern,
C.Ulens.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
E2543.
[DOI no: ]
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PubMed id
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Abstract
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The α7 nicotinic acetylcholine receptor (nAChR) belongs to the family of
pentameric ligand-gated ion channels and is involved in fast synaptic signaling.
In this study, we take advantage of a recently identified chimera of the
extracellular domain of the native α7 nicotinic acetylcholine receptor and
acetylcholine binding protein, termed α7-AChBP. This chimeric receptor was used
to conduct an innovative fragment-library screening in combination with X-ray
crystallography to identify allosteric binding sites. One allosteric site is
surface-exposed and is located near the N-terminal α-helix of the extracellular
domain. Ligand binding at this site causes a conformational change of the
α-helix as the fragment wedges between the α-helix and a loop homologous to
the main immunogenic region of the muscle α1 subunit. A second site is located
in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite
the agonist binding site and corresponds to a previously identified site
involved in positive allosteric modulation of the bacterial homolog ELIC. A
third site is located at a pocket right below the agonist binding site. Using
electrophysiological recordings on the human α7 nAChR we demonstrate that the
identified fragments, which bind at these sites, can modulate receptor
activation. This work presents a structural framework for different allosteric
binding sites in the α7 nAChR and paves the way for future development of novel
allosteric modulators with therapeutic potential.
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