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PDBsum entry 2jpr
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Viral protein
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PDB id
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2jpr
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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 the antiviral assembly inhibitor cap-1 complex with the HIV-1 ca protein.
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Authors
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B.N.Kelly,
S.Kyere,
I.Kinde,
C.Tang,
B.R.Howard,
H.Robinson,
W.I.Sundquist,
M.F.Summers,
C.P.Hill.
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Ref.
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J Mol Biol, 2007,
373,
355-366.
[DOI no: ]
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PubMed id
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Abstract
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The CA domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein
plays critical roles in both the early and late phases of viral replication and
is therefore an attractive antiviral target. Compounds with antiviral activity
were recently identified that bind to the N-terminal domain of CA (CA(N)) and
inhibit capsid assembly during viral maturation. We have determined the
structure of the complex between CA(N) and the antiviral assembly inhibitor
N-(3-chloro-4-methylphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methyl)-sulfanyl]ethyl}-urea)
(CAP-1) using a combination of NMR spectroscopy and X-ray crystallography. The
protein undergoes a remarkable conformational change upon CAP-1 binding, in
which Phe32 is displaced from its buried position in the protein core to open a
deep hydrophobic cavity that serves as the ligand binding site. The aromatic
ring of CAP-1 inserts into the cavity, with the urea NH groups forming hydrogen
bonds with the backbone oxygen of Val59 and the dimethylamonium group
interacting with the side-chains of Glu28 and Glu29. Elements that could be
exploited to improve binding affinity are apparent in the structure. The
displacement of Phe32 by CAP-1 appears to be facilitated by a strained
main-chain conformation, which suggests a potential role for a Phe32
conformational switch during normal capsid assembly.
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Figure 4.
Figure 4. Representative CAP-1:CA^N structure calculated by
restrained molecular dynamics using the hybrid X-ray/NMR
approach. (a) Stereo view of the CAP-1 binding with observed
NOEs (broken black lines) and potential hydrogen bonds (broken
red lines) labeled. The side-chain of Phe32, which is displaced
from the core upon CAP-1 binding, is also shown. (b)
Electrostatic surface representation of the CAP-1 binding site
showing the insertion of the CAP-1 aromatic ring into the pocket
vacated by Phe32.
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Figure 6.
Figure 6. (a) Model of the HIV-1 CA^N hexamer of the mature
capsid lattice modeled on the MLV CA^N structure.^17 CAP-1 is
shown in stick representation. (b) Orthogonal view. The
approximate location of CA^C is indicated.
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The above figures are
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2007,
373,
355-366)
copyright 2007.
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