AIDSWEEKLY Plus, Monday, December 8, 1997
Daniel J. DeNoon, Senior Editor
Researchers have solved the atomic structure of a crucial portion of the HIV envelope.
The finding is expected to lead to new small-molecule candidate AIDS therapies as well as to new targets for HIV vaccines.
HIV must bind to host-cell chemokine receptors in order to fuse with the cell membrane. This crucial fusion process occurs when the receptors trigger the release of the coiled spring of HIV's gp41 transmembrane molecule, penetrating the cell membrane. But until now, the exact structure of this critical, highly conserved component of HIV has been shrouded in mystery.
"These crystal structures ... provide detailed three-dimensional structural information defining the interaction between the N- and C- terminal peptides of gp41, and therefore may lead to new therapeutic and prophylactic strategies targeting HIV-1 entry," wrote Kemin Tan of the Dana-Farber Cancer Institute and colleagues in the Proceedings of the National Academy of Sciences ("Atomic Structure of a Thermostable Subdomain of HIV-1 gp41," PNAS, 1997;94:12303-8).
Tan et al. noted that the extraviral portion of gp41 (the ectodomain) is the most conserved portion of the HIV envelope. It contains two hydrophobic repeat sequences predicted to form the unsprung coil.
In a series of protein dissection experiments, the researchers created a soluble, (alpha)-helical, trimeric, protease-resistant complex within gp41. This complex is made up of N-terminal and C- terminal segments of the gp41 ectodomain.
By using a flexible molecular linker to connect the two truncated peptides N-51 and C-43 that compose this complex, Tan et al. generated the thermostable subdomain N34(L6)C28 and determined its crystal structure at a resolution of 2.4 Angstrom.
Other workers recently have reported the crystal structures of (alpha)-helical domains of gp41 (Chan et al., Cell, 1997;89:263-73; Weissenhorn et al., Nature, 1997;387:426-30).
"Comparison of these crystal structures shows that the minimal N34(L6)C28 subdomain imparts the key determinants of the core structure of gp41," Tan et al. announced.
This work was supported by Cornell University Medical College and by National Institutes of Health Grant AI27336.
The corresponding author for this study is Jia-Huai Wang, Laboratory of Immunobiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115. E-mail: <jwang@red.dfci.harvard.edu>.
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