NEW YORK--Using x-ray crystallography, researchers have managed to
catch an HIV surface glycoprotein (gp120) in the act of binding to a
CD 4T-cell receptor (Figure 1). The
images are a collaborative effort led by researchers from Columbia
University College of Physicians & Surgeons and Dana-Farber
"The crystal structure tells us how the virus is able to bind to
the receptor at the same time that it remains sufficiently changeable
to avoid immune detection," said Wayne Hendrickson, PhD,
professor of biochemistry and molecular biophysics, Columbia University.
Could Boost Vaccine Design
Peter Kwong, PhD, associate research scientist at Columbia, added:
"Knowing the structure down to the atomic details will provide
valuable clues for vaccine design." The research was reported in
the June 19 issue of Science, and the June 18 issue of Nature.
X-ray crystallography is a technique that passes x-rays through a
crystal from many angles, determines their patterns of diffraction,
and then assembles the data to reveal the crystals
3-dimensional structure. Use of the technique, however, requires that
a compound be crystallized, which was no small feat for gp120.
"The mechanisms that HIV has to protect itself from the immune
system also make it difficult to crystallize," Dr. Kwong said.
To get gp120 to crystallize, the researchers snipped off parts of it,
using genetic clues from the virology team at Dana-Farber led by
Joseph Sodroski, MD.
They eventually obtained a structure for the core of gp120 bound to
both the CD4 receptor and a stabilizing antibody. This antibody also
marks the binding site for the chemokine co-receptor. Once gp120
binds to CD4, its shape changes in a way that enables it also to bind
to the nearby chemokine receptor. Only then can the membranes of
virus and human cell fuse and infection proceed.
The crystal structure has revealed potential new drug targets. Said
Dr. Kwong, "At the interface of the gp120/CD4 receptor is a
large cavity just begging to be filled with a high-affinity inhibitor."