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PDBsum entry 2r3c
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Viral protein/viral protein inhibitor
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PDB id
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2r3c
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Contents |
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47 a.a.
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43 a.a.
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15 a.a.
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16 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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Potent d-Peptide inhibitors of HIV-1 entry.
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Authors
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B.D.Welch,
A.P.Vandemark,
A.Heroux,
C.P.Hill,
M.S.Kay.
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Ref.
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Proc Natl Acad Sci U S A, 2007,
104,
16828-16833.
[DOI no: ]
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PubMed id
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Abstract
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During HIV-1 entry, the highly conserved gp41 N-trimer pocket region becomes
transiently exposed and vulnerable to inhibition. Using mirror-image phage
display and structure-assisted design, we have discovered protease-resistant
D-amino acid peptides (D-peptides) that bind the N-trimer pocket with high
affinity and potently inhibit viral entry. We also report high-resolution
crystal structures of two of these D-peptides in complex with a pocket mimic
that suggest sources of their high potency. A trimeric version of one of these
peptides is the most potent pocket-specific entry inhibitor yet reported by
three orders of magnitude (IC(50) = 250 pM). These results are the first
demonstration that D-peptides can form specific and high-affinity interactions
with natural protein targets and strengthen their promise as therapeutic agents.
The D-peptides described here address limitations associated with current
L-peptide entry inhibitors and are promising leads for the prevention and
treatment of HIV/AIDS.
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Figure 2.
Fig. 2. Structural analysis of the IQN17:2K-PIE1 inhibitor
complex. (A) IQN17, consisting of IQ (orange) and gp41 (N17,
gray) segments, with inhibitors (green, yellow, and purple)
located in the canonical gp41 binding pockets. The purple
inhibitor is mostly occluded in this view. (B) Omit map for
2K-PIE1 contoured at 3.0 x rmsd. Five of the eight pocket
residues (gray, HXB2 numbering) that make hydrophobic contacts
with 2K-PIE1 (green) are shown. Two hydrogen bonds (black) at
the binding interface are also shown. (C) Overlay of D10-p1
(slate) and 2K-PIE1 (green) superposed by alignment of the IQN17
trimers. Intramolecular disulfide bonds (solid yellow) are also
shown. (D) A slab view through the center of 2K-PIE1 (green)
reveals an intact hydrophobic core (black) that excludes water.
(E) A similar view of D10-p1 (slate) reveals the presence of
several water molecules (red) in its core that nearly form a
water channel. (F) End-on view of the complex (same color scheme
as A) in which the surface from the last three residues of IQN17
have been removed. This view illustrates the packing of the
inhibitor into the deep hydrophobic pocket. dK2 (blue),
equivalent to the N-terminal Lys in PIE7 used for cross-linking,
is highlighted.
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Figure 4.
Fig. 4. Structural analysis of the IQN17:2K-PIE1 and
IQN17:PIE7 inhibitor complexes. Shown is a comparison of unique
polar contacts observed in the 2K-PIE1 (A) and PIE7 (B)
costructures (described in the text).
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