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PDBsum entry 2l6e
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Viral protein/inhibitor
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PDB id
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2l6e
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References listed in PDB file
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Key reference
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Title
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Solution structure of a hydrocarbon stapled peptide inhibitor in complex with monomeric c-Terminal domain of HIV-1 capsid.
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Authors
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S.Bhattacharya,
H.Zhang,
A.K.Debnath,
D.Cowburn.
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Ref.
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J Biol Chem, 2008,
283,
16274-16278.
[DOI no: ]
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PubMed id
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Abstract
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The human immunodeficiency virus type 1 (HIV-1) capsid protein plays a critical
role in virus core particle assembly and is an important target for novel
therapeutic strategies. In a previous study, we characterized the binding
affinity of a hydrocarbon stapled helical peptide, NYAD-1, for the capsid
protein (K(d) approximately 1 mum) and demonstrated its ability to penetrate the
cell membrane (Zhang, H., Zhao, Q., Bhattacharya, S., Waheed, A. A., Tong, X.,
Hong, A., Heck, S., Goger, M., Cowburn, D., Freed, E. O., and Debnath, A. K.
(2008) J. Mol. Biol. 378, 565-580). In cell-based assays, NYAD-1 colocalized
with the Gag polyprotein during traffic to the plasma membrane and disrupted the
formation of mature and immature virus particles in vitro systems. Here, we
complement the cellular and biochemical data with structural characterization of
the interactions between the capsid and a soluble peptide analogue, NYAD-13.
Solution NMR methods were used to determine a high resolution structure of the
complex between the inhibitor and a monomeric form of the C-terminal domain of
the capsid protein (mCA-CTD). The intermolecular interactions are mediated by
the packing of hydrophobic side chains at the buried interface and unperturbed
by the presence of the olefinic chain on the solvent-exposed surface of the
peptide. The results of the structural analysis provide valuable insight into
the determinants for high affinity and selective inhibitors for HIV-1 particle
assembly.
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Figure 1.
FIGURE 1. A, the helical representation of a single
structure of mCA-CTD (148–221) and NYAD-13 (2–11). The
secondary structure consists of an N-terminal 3[10] helix, a
type 1 β-turn, and a four-helix bundle. B, the side chains
(blue) from residues in helix I and helix II are represented in
the ensemble of NMR structures. For clarity, the peptide has
been removed from the structure. Conserved residues from the MHR
motif are colored in magenta. The structural representations
were generated in MOLMOL 2.1 (30).
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Figure 2.
FIGURE 2. Structural details of intermolecular contacts
with ribbon representation of the protein (blue) and peptide
(pink) backbone. A, the top view of the binding surface displays
the interactions between the side chains of Phe-3 and Tyr-10
from the peptide and helix I and II of mCA-CTD. B, the side view
of the complex displays the interactions that anchor Leu-6 and
Tyr-9 from the peptide using Leu-211 and Met-215 from helix IV.
C, the top view of the x-ray structure of CAI in complex with
CA-CTD (2BUO). D, superposition of the backbone C  atoms of
CA-CTD (pink) and mCA-CTD (green) based on alignment generated
from residues in helix I, helix III, and helix IV (r.m.s.d. =
0.8 Å). When helix II is included, the r.m.s.d. increases
to 1.3 Å. Residues that are important for binding the
target peptide and rearranged through the helix movement are
indicated in the figure. The PDB code for CA-CTD structure used
in the alignment is 1A8O. The figures were generated in MOLMOL
2.1 (30).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
16274-16278)
copyright 2008.
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