Biology Reference
In-Depth Information
V3-containing gp120-CD4-Fab complex.
167
The increased exposure
of V3 in the CD4-bound conformation could be explained by a
rearrangement of the trimer in the first model, or by a conformational
change involving the V3 loop in the second model.
The conserved
co-receptor binding site
, comprising the bridg-
ing sheet
76
and associated regions, is thought to be largely inaccessi-
ble in the trimer. Experimental data support this concept, since most
CD4-induced (CD4i) surface-specific mAbs cannot access their epi-
topes on the CD4-unligated Env trimer, as evidenced by weak or
absent neutralization. It is possible that the V3 loop may be involved
in protecting the co-receptor binding sites from antibody recognition
and binding.
A trimer model has been proposed previously in which the inner
domain of gp120 points toward the gp120-gp41 interface and the
outer domain extends outward.
76
Such a model is inconsistent with
the orientation of the major axis of the ellipsoidal gp120 density
within the density corresponding to gp120 in our structure. In this
previous model, the V3 loop is exposed to solvent and the co-receptor
binding site is buried at the trimer interface. The two fittings pro-
posed by Zanetti
et al
. clearly suggest that either the V3 loop is
also pointing toward the trimer interface, or the co-receptor bind-
ing site is on the outside of the trimer, and protected from solvent
by V3.
178
It is likely that the Env complex exhibits some conforma-
tional flexibility.
In the context of trimeric Env, the gp41 stem appears as a com-
pact structure with no obvious separation between the three
monomers.
178
The membrane-proximal region of gp41 is character-
ized by a highly conserved hydrophobic region, which is thought to
mediate trimer self-assembly.
184
Furthermore, the density correspon-
ding to the gp41 stem region is shorter and slightly wider than the
post-activation coiled-coil conformation,
185
in agreement with the
hypothesis that a dramatic conformational change is required for
gp41 to extend toward, and insert into, the target cell membrane.
The shape of the complex suggests a new model for the Env trimer
organization. The volumes are consistent with the assignment of
the globular domains to gp120 and the stem to gp41. The gp120
