The resulting crystallography data provided that fine-grained picture of CCR5’s HIV-resistant conformation. The data also revealed maraviroc’s precise binding site on CCR5—a site from which the drug molecule clearly influences how the receptor works, even though it is separate from the sites on the receptor that are thought to be used by HIV. The maraviroc binding site is also different from the site used by CCR5’s natural binding-partners, a set of immune proteins called chemokines. Maraviroc thus appears to work against HIV indirectly—not by physically blocking the virus, but by locking the receptor structure into an HIV-insensitive conformation.
“Structural details can offer tremendous insight into how proteins and drugs work, also aiding the development of therapeutic agents,” said Peter Preusch, PhD, of the National Institute of General Medical Sciences, which helped fund the research along with another component of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases. “This study provides knowledge about the interactions between maraviroc and CCR5, a target for anti-HIV therapy, that helps us understand how the drug works at the molecular level and could enable further explorations of HIV biology and approaches to improve drugs targeting such interactions.”
Comparison of the CCR5 structure with the previously determined CXCR4 structure also provided hints about an important aspect of HIV evolution during infections. Most HIV infections start by using only CCR5 as a co-receptor for cell entry, but in time the virus often switches its co-receptor usage from CCR5 to CXCR4. That opens up more cell types to HIV infection, and the further spread of the virus inside the body is liable to speed up the disease progression towards full-blown AIDS and death.
The new data suggest that the distinction between CCR5 and CXCR4 as co-receptors for HIV infection boils down to relatively subtle differences in structural shapes and electric charge distributions in the HIV binding region—differences that will be of interest to HIV drug developers.
“Knowing the CXCR4 structure and now the CCR5 structure at this level of detail should accelerate the development of drugs that can block HIV by using both of these co-receptors,” said Wu.
She and her colleagues now plan to follow up with structural studies of CCR5 and CXCR4 in complex with the HIV envelope protein gp120 and CD4 to obtain even more informative pictures of the process of viral infection.
Soon after the structure determination of CCR5, SIMM performed structure-based drug design and has obtained several drug lead compounds with more potent antiviral efficacies than maraviroc, which further proves the importance of CCR5 structure on the development of HIV theraputics.