Biology Reference
In-Depth Information
Current Structural Information that may be used for
Designing new Immunogens
While the efforts were directed to solve the crystal structure of Env
trimer, and to address the technical challenges associated with it, two
groups have applied a low-resolution technique (i.e. Cryo-EM) to cir-
cumvent the problems associated with crystallization and to provide
the structural information on the Env trimer.
178,179
Zulleti
et al
. have
two best-fitted Cryo-EM three-dimensional desnsities, and both of
these structures suggest that: i) all the glycans are pointing outward
from the surface of the trimer, and solvent exposed, which is consis-
tent with the glycan shield model proposed by different investigators
to protect the virus against the neutralizing antibodies
120,180
; ii) the vari-
able regions V4 and V5 are positioned on the top surface of the com-
plex, an orientation that would facilitate their recognition by
antibodies
181
; iii) the V1V2 loop extends outward, implying good sol-
vent exposure, and in addition it is possible that the interaction of
V1V2 loop and the co-receptor binding site in the monomer may
limit the access of the co-receptor binding site to antibodies; iv) the
CD4 binding surface is exposed on the outer edge of each gp120 pro-
tomer, and is oriented such that access to membrane-associated CD4
on the target cell is possible; and v) the two models differ significantly
with regard to the orientation and exposure of V3 loop, and the ori-
entation of co-receptor binding sites. In the
first model
, the
V3 base
points toward the trimer interface
running roughly parallel to the
3-fold symmetry axis, being partially exposed in the cavities between
the lobes. In this trimer model, the V3 loop would be substantially
masked by packing into the trimer axis, potentially reinforced by
inter-V3 bonding. In the
second model
, the
V3 loop is oriented out-
ward in solvent exposed phase
. In addition, V3 seems to be highly
flexible in the CD4-unbound trimer. After Env binds to CD4 it
induces a conformational change in Env that increases V3 exposure.
This is supported experimentally by the increased accessibility of the
V3 loop in the Env trimer to antibody binding and enzymic proteol-
ysis subsequent to CD4 engagement.
182,183
It is also consistent with
the highly exposed nature of the V3 loop in the structure of the
