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PDBsum entry 2c9t
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Receptor/toxin
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PDB id
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2c9t
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Contents |
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(+ 4 more)
205 a.a.
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(+ 2 more)
13 a.a.
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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 determinants of selective alpha-Conotoxin binding to a nicotinic acetylcholine receptor homolog achbp.
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Authors
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C.Ulens,
R.C.Hogg,
P.H.Celie,
D.Bertrand,
V.Tsetlin,
A.B.Smit,
T.K.Sixma.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
3615-3620.
[DOI no: ]
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PubMed id
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Abstract
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The nicotinic acetylcholine receptor (nAChR) is the prototype member of the
superfamily of pentameric ligand-gated ion channels. How the extracellular
ligand-binding domain coordinates selective binding of ligand molecules to
different subtypes of the receptor is unknown at the structural level. Here, we
present the 2.2-A crystal structure of a homolog of the ligand-binding domain of
the nAChR, Aplysia californica AChBP (Ac-AChBP), in complex with alpha-conotoxin
ImI. This conotoxin is unique in its selectivity toward the neuronal alpha3beta2
and alpha7 nAChR, a feature that is reflected in its selective binding to
Ac-AChBP compared with other AChBP homologs. We observe a network of
interactions between the residues of the ligand-binding site and the toxin, in
which ImI Arg-7 and Trp-10 play a key role. The toxin also forms interactions in
the ligand-binding site that were not seen in the complex of Ac-AChBP with
PnIA(A10L D14K), a conotoxin variant that lacks binding selectivity to AChBP
homologs. In combination with electrophysiological recordings obtained by using
the wild-type alpha7 nAChR and L247T mutant, we show that conotoxin ImI inhibits
ion conduction by stabilizing the receptor in a desensitized conformation.
Comparison of the Ac-AChBP-ImI crystal structure with existing AChBP structures
offers structural insight into the extent of flexibility of the interface loops
and how their movement may couple ligand binding to channel gating in the
context of a nAChR.
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Figure 2.
Fig. 2. Crystal structure of  -conotoxin ImI bound to
Ac-AChBP viewed along the fivefold axis. Conotoxins are in red.
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Figure 4.
Fig. 4. Molecular contacts at the toxin–receptor
interface. (A and B) Details of molecular contacts between
Ac-AChBP and -conotoxin PnIA(A10L
D14K) (A) and -conotoxin ImI (B). The
conotoxin is shown in red, the principal binding side in yellow,
and the complementary binding side in blue. Disulfide bridges
are green. Dashed lines indicate H-bonds or salt bridges. (C)
Sequence alignment of Ac-AChBP, Ls-AChBP, and [7],
[9], [3],
 [4]
nAChRs. Sequence numbering at the top is for Ac-AChBP and at the
bottom is for [7] nAChR. Residues of
the principal binding side that interact with -conotoxin ImI are
shown in yellow; residues of the complementary binding side are
in blue. Contacts that are present in the complex with ImI, but
not in the complex with PnIA(A10L D14K), are labeled with  below
the alignment.
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