posted on 2016-02-20, 10:12authored byIndira H. Shrivastava, Kaylee Wendel, Judith
M. LaLonde
Binding of the viral spike drives cell entry and infection
by HIV-1
to the cellular CD4 and chemokine receptors with associated conformational
change of the viral glycoprotein envelope, gp120. Crystal structures
of the CD4–gp120–antibody ternary complex reveal a large
internal gp120 cavity formed by three domainsthe inner domain,
outer domain, and bridging sheet domainand are capped by CD4
residue Phe43. Several structures of gp120 envelope in complex with
various antibodies indicated that the bridging sheet adopts varied
conformations. Here, we examine bridging sheet dynamics using a crystal
structure of gp120 bound to the F105 antibody exhibiting an open bridging
sheet conformation and with an added V3 loop. The two strands of the
bridging sheet β2/β3 and β20/β21 are dissociated
from each other and are directed away from the inner and outer domains.
Analysis of molecular dynamics (MD) trajectories indicates that the
β2/β3 and β20/β21 strands rapidly rearrange
to interact with the V3 loop and the inner and outer domains, respectively.
Residue N425 on β20 leads the conformational rearrangement of
the β20/β21 strands by interacting with W112 on the inner
domain and F382 on the outer domain. An accompanying shift is observed
in the inner domain as helix α1 exhibits a loss in helicity
and pivots away from helix α5. The two simulations provide a
framework for understanding the conformational diversity of the bridging
sheet and the propensity of the β20/β21 strand to refold
between the inner and outer domains of gp120, in the absence of a
bound ligand.