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PDBsum entry 1r0x
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Transport protein
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PDB id
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1r0x
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of nucleotide-Binding domain 1 of the cystic fibrosis transmembrane conductance regulator.
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Authors
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H.A.Lewis,
S.G.Buchanan,
S.K.Burley,
K.Conners,
M.Dickey,
M.Dorwart,
R.Fowler,
X.Gao,
W.B.Guggino,
W.A.Hendrickson,
J.F.Hunt,
M.C.Kearins,
D.Lorimer,
P.C.Maloney,
K.W.Post,
K.R.Rajashankar,
M.E.Rutter,
J.M.Sauder,
S.Shriver,
P.H.Thibodeau,
P.J.Thomas,
M.Zhang,
X.Zhao,
S.Emtage.
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Ref.
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EMBO J, 2004,
23,
282-293.
[DOI no: ]
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PubMed id
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Abstract
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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding
cassette (ABC) transporter that functions as a chloride channel.
Nucleotide-binding domain 1 (NBD1), one of two ABC domains in CFTR, also
contains sites for the predominant CF-causing mutation and, potentially, for
regulatory phosphorylation. We have determined crystal structures for mouse NBD1
in unliganded, ADP- and ATP-bound states, with and without phosphorylation. This
NBD1 differs from typical ABC domains in having added regulatory segments, a
foreshortened subdomain interconnection, and an unusual nucleotide conformation.
Moreover, isolated NBD1 has undetectable ATPase activity and its structure is
essentially the same independent of ligand state. Phe508, which is commonly
deleted in CF, is exposed at a putative NBD1-transmembrane interface. Our
results are consistent with a CFTR mechanism, whereby channel gating occurs
through ATP binding in an NBD1-NBD2 nucleotide sandwich that forms upon
displacement of NBD1 regulatory segments.
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Figure 1.
Figure 1 Domain organization of CFTR. The five domains of CFTR
are shown. Also indicated is a putative nucleotide-binding
domain association in which the ATP-binding site of one NBD is
opposed by the signature sequence of the other NBD. Inactivity
at the NBD1 ATP-binding site is indicated by Ser residues in
place of the catalytic Glu and His in addition to His residues
substituted for the Gln and central Gly in the NBD2 signature
sequence.
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Figure 4.
Figure 4 Close-up on ATP binding by mNBD1. (A) Canonical
hydrogen bonding interactions in Mg-ATP mNBD1. Some relevant
hydrogen bonds are indicated as green lines. Some residues in
the foreground and background have been removed to clarify the
interactions, here and in (B) and (C). (B) Differences in
adenine base recognition from other ABC domains. Left: adenine
stacks against Tyr11 of MJ0796 (PDB ID code 1L2T). Right:
adenine of ATP makes edge-to-face interactions with Phe430 of
mNBD1. (C) Added structure in phosphorylated mNBD1. The ATP
molecule plus magnesium in blue, the additional mNBD1 residues
observed in the phosphorylated state in white, the phosphate
atoms of Ser422 and Ser660 in brown, and the remainder of the
mNBD1 structure in yellow are shown.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2004,
23,
282-293)
copyright 2004.
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