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Figure 1.
Figure 1. Model of HIV Membrane Fusion and Structure of the
gp41 CoreSchematic representation of a working model for HIV
membrane fusion (for review[9]). In the native state of the
trimeric gp120/gp41 complex (“Native”), the fusion peptide
and N-peptide regions of gp41 are not exposed. Following
interaction with cellular receptors (CD4 and coreceptor), a
conformational change results in formation of the transient
prehairpin intermediate (“Pre-Hairpin”), in which the fusion
peptide regions (red lines) are inserted into the cell membrane
and the coiled coil of the N-peptide region of gp41 (indicated
as “N”) is exposed. However, the C-peptide region of gp41
(indicated as “C”) is constrained and unavailable for
interaction with the coiled coil. Thus, exogenous C-peptides can
bind to the prehairpin intermediate and inhibit fusion in a
dominant-negative manner (“Inhibited”). In the absence of
inhibitors, the prehairpin intermediate resolves to the hairpin
structure and membrane fusion results (“Hairpin/Fusion”),
although it is not known whether hairpin formation precedes
membrane fusion per se. The C-peptides discussed in this paper
(and corresponding residues in gp41, numbered according to their
position in gp160 of the HXB2 HIV-1 strain) are as follows: C34
[628–661]; DP178, also called T-20 [638–673]; and T649
[628–663]. Adapted from [9].The inset depicts the 2.0 Å
X-ray crystal structure of N36/C34, a peptide version of the
HIV-1 gp41 core ([10]). Three central N-peptides form a coiled
coil, shown here as a surface representation, and three helical
C-peptides pack along conserved grooves on the surface of the
coiled-coil trimer. There are three symmetry-related hydrophobic
pockets on the surface of the N-peptide coiled coil (shaded).
The pocket region is highly conserved among HIV-1 isolates.
There are 11 residues that comprise the lining of the
hydrophobic pocket (see Figure 7 of [10]): Leu-565, Leu-566,
Leu-568, Thr-569, Val-570, Trp-571, Gly-572, Ile-573, Lys-574,
Leu-576, and Gln-577 of HXB2. These 11 residues are completely
conserved in 158 of 202 fully sequenced M group HIV-1 strains
(HIV Sequence Database [1998/1999 alignments], Los Alamos
National Laboratory, ). Of the remaining 44 isolates, 33 possess
only a single conservative methionine substitution for Leu-565.
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