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Research Themes Drug discovery

CCR5 and HIV Infection

SBKB [doi:10.3942/psi_sgkb/fm_2015_1]
Featured System - January 2015
Short description: A new PSI structure shows how the anti-HIV drug maraviroc locks the coreceptor CCR5 in an inactive state.

Cells of the immune system are in constant communication, notifying each other about dangers and deciding how to mobilize the best defense. Chemokines are a central part of this communication system. They are small proteins that are secreted by one cell and then sensed by receptors on the surface of another cell, which tell it the proper direction to go. PSI researchers at the GPCR Network, in collaboration with researchers at the Chinese Academy of Sciences, have recently solved the structure of one of these receptors, and revealed how it may be used to fight infection by HIV.

Close-up on CCR5

CCR5 is a chemokine receptor that controls the migration of cells in the blood. The structure, shown here from PDB entry 4mbs, reveals that it is a prototypical GPCR, with the classic arrangement of seven helices that zigzag across the membrane. The chemokine-binding site is in a deep pocket on the outer side (shown at the top here). When it binds to a chemokine, the signal is transmitted across the membrane to the inside of the cell, where it mobilizes a cascade of signals centered around inhibitory G-proteins.

Blocking the Signal

The CCR5 structure also includes maraviroc (shown here in magenta), the first anti-HIV drug designed to target the host cell rather than the virus. Maraviroc binds deep in the receptor pocket and locks the receptor in an inactive state. In the process, it also blocks attachment by HIV, stopping infection of the cell. In a similar way, a rare mutation of the receptor also provides resistance from viral infection. Some people have an inactive form of CCR5 with one of the extracellular loops deleted. The virus then has nothing to recognize and can't attach to the cell.


Chemokines

CCR5 binds to four similar chemokines, shown here from PDB entries 1b53, 1hum, 1rto and 1esr. They are all small proteins that adopt a similar folding pattern, but recent research has shown that they are quite variable in the way they oligomerize. All of these structures are dimers, but several have been shown to form higher-order oligomers. These oligomers are thought to be important for association of chemokines on the surfaces of cells, which helps to tether the chemokines in their proper functional place and direct the path that migrating cells should take. The monomeric form, however, is thought to be the form that binds to the receptor and promotes cell migration.


Signaling in CCR5

CCR5 has many moving parts that work together to sense and transmit the signal. The N-terminus of the chain and a large loop between helices, both shown here in green, bind to chemokines. Then one tail of the chemokine binds in the receptor pocket, causing shifts in shape that propagates the signal across the membrane. Several amino acids in the pocket, including a tryptophan shown here in turquoise, are involved in sensing the presence of the chemokine. The drug maraviroc locks these amino acids in their inactive state. To explore this structure in 3D, the JSmol tab below displays an interactive JSmol.

CCR5 and Maraviroc (PDB entry 4mbs)

Research has shown that two sites on CCR5 are important for the recognition of chemokines. A loop on the surface and the end of the receptor chain, both shown here in green, bind to the main body of the chemokine. Then, the end of the chemokine chain binds in the receptor pocket, which is occupied by the drug maraviroc (magenta) in this structure. Use the buttons to display a key tryptophan involved in the interaction, and the small protein rubredoxin which was spliced into CCR5 to assist with crystallization.

References

  1. 4mbs: Tan, Q. et al. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341, 1387-1390 (2013).

  2. Wilkin, T. J. & Gulick, R. M. CCR5 antagonism in HIV infection: current concepts and future opportunities. Annu. Rev. Med. 63, 81-93 (2012).

  3. Salanga, C. L. & Handel, T. M. Chemokine oligomerization and interactions with receptors and glycosaminoglycans: the role of structural dynamics in function. Exp. Cell Res. 317, 590-601 (2011).

  4. 1esr: Blaszczyk, J. et al. Complete crystal structure of monocyte chemotactic protein-2, a CC chemokine that interacts with multiple receptors. Biochem. 39, 14075-14081 (2000).

  5. 1b53: Czaplewski, L. G. et al. Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES. J. Biol. Chem. 274, 1677-16084 (1999).

  6. 1rto: Skelton, N. J., Aspiras, F., Ogez, J. & Schall, T. J. Proton NMR assignments and solution conformation of RANTES, a chemokine of the C-C type. Biochem. 34, 5329- 5342 (1995).

  7. 1hum: Lodi, P. J. et al. High-resolution solution structure of the beta chemokine hMIP-1 beta by multidimensional NMR. Science 263, 1762-1767 (1994).

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