[ Back to EurekAlert! ] Public release date: 12-Sep-2013
[ | E-mail Share Share ]

Contact: Natasha Pinol
npinol@aaas.org
202-326-6440
American Association for the Advancement of Science

Ready for its close-up: 1 of HIV's entrance points

Scientists determine high-resolution structure of 1 of 2 co-receptors used by HIV

Scientists have gotten the first close look at one of two co-receptors HIV uses to get its foot in the door of the immune system, a new study reports. Their insights could lead to better HIV drugs.

CCR5, a receptor on the surface of human cells, is one of two main entry points the HIV virus uses to initiate its attack on the human immune system; by binding to it, an HIV protein can fuse to the cell membrane beneath, ultimately digging its way inside the cell.

The other receptor that HIV uses to perform this feat is CXCR4.

Both CCR5 and CXCR4 belong to a family of receptor proteins called G-protein-coupled receptors, or GPCRs, which mediate a range of functions in the body and are thus important drug targets.

Only recently, however, have scientists been able to image GPCRs at high resolution—a critical step for drug design. "Structural studies of GPCRs are enormously challenging," explained Beili Wu, a researcher from the Chinese Academy of Sciences' Shanghai Institute of Materia Medica who participated in the study.

CXCR4's structure has already been solved, but even so, aspects of how this receptor recognizes and binds to HIV viral proteins remain unclear.

Now, in a new study reported in the 13 September issue of the journal Science, Wu and colleagues have gotten the first precise look at CCR5, which HIV strains use more often.

To do this, the researchers leveraged a drug for treatment of HIV-1 called Maraviroc. This drug is a CCR5 receptor antagonist that works by binding the co-receptor so it's unavailable to circulating HIV.

Wu explained that her team's previous work to image CXCR4 at high resolution facilitated their progress this time around, too. "Breakthroughs in GPCR structural biology in recent years, especially our previous success of solving human CXCR4 structures, helped us to better understand the protein behavior of the more challenging CCR5 receptor," she said.

Wu and her colleagues allowed Maraviroc to bind an engineered CCR5 receptor and then purified and crystallized the resulting receptor/drug complex at 2.7 Angstroms—a very high resolution.

Observing the bound complex (in which the receptor wasn't inhibited, so to speak, but rendered inactive and thus unreceptive to HIV) provided insights into the molecular pathway by which HIV fuses with cells. Critically, these observations illustrated the molecular-level quirks that allow some HIV mutants to escape CCR5 inhibitors; this happens when the CCR5 co-receptor assumes an odd dome shape that lowers its affinity for the inhibitor, leaving the receptor open, available for HIV binding.

The study also revealed aspects of the CCR5/drug complex distinct from the structure of the other co-receptor: CXCR4 bound to its inhibitor. The CCR5/drug complex binds more deeply in the target cell membrane, for example, and it also occupies a larger area.

Structural comparisons between the two HIV co-receptors helped to shed light on why an HIV molecule chooses one co-receptor over the other.

"Although CCR5 and CXCR4 share very similar overall architecture," Wu said, "there are very small differences within the ligand binding pockets of the two co-receptors, and they likely result in the recognition of distinct HIV-1 strains by different co-receptors."

These and other insights will assist scientists in improving existing HIV drugs based on CCR5 inhibition, and also in creating new HIV drugs.

"We hope that the structure we determined can be used to understand the molecular details of the current viral strains of HIV entry, to develop new molecules that can inhibit both CXCR4 and CCR5 receptors, and to block future strains that might emerge and be addressed with second generation HIV entry inhibitors," Wu said.

###

This project was supported by "National Basic Research Program of China" grants 2012CB518000 and 2012CB910400, National Institutes of Health R01 AI100604, National Science Foundation of China grants 31270766, 31170683 and 81025017, and Shanghai Science and Technology Committee grants 11JC1414800 and 12PJ1410500.



[ Back to EurekAlert! ] [ | E-mail Share Share ]

 


AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.