PSI Structural Biology Knowledgebase

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CXCR4

SBKB [doi:10.3942/psi_sgkb/fm_2011_1]
Featured System - January 2011
Short description: The GPCR (G protein-coupled receptor) community is suffering from an embarrassment of riches.

3emm The GPCR (G protein-coupled receptor) community is suffering from an embarrassment of riches. For many years, structure-based studies relied on atomic structures of rhodopsin, and research was forced to extrapolate from these using homology models. But in the past few years, PSI researchers have revolutionized the field with new structures and new insights. A collection of five structures of CXCR4, solved by a team of researchers at the PSI GPCR network, is the most recent installment in this exciting story.

Signaling in Health and Disease

CXCR4 is a chemokine receptor that regulates the migration of cells in the immune system. Chemokine receptors typically interact with a variety of chemokines, but CXCR4 is an exception, and is specific for the chemokine CXCL12. Together, they normally play an essential role in the development of blood cells, but they are also important in disease. For instance, communication through CXCR4 may promote the many pathological changes in cancer cells, including formation of metastases and abnormal growth of blood vessels. CXCR4 also plays a central role in infection by HIV, since it is the co-receptor that guides the virus into cells.

CXCR4 in Action

The structure of CXCR4 revealed the signature core of GPCRs: a bundle of seven alpha helices that criss-cross through the cell membrane. These are connected by a series of loops that are exposed on the two sides of the membrane and perform much of the work of recognizing the chemokine and passing the signal inside. The binding site is a cup-shaped depression on the outer surface. Crystal structures were obtained with a large cyclic peptide bound in the active site (shown at the top here from PDB entry 3oe0), suggesting how the chemokine might bind, and also with a small inhibitor bound (shown below from PDB entry 3odu), providing a place to start for design of anti-HIV drugs.

Solving the Structure

Membrane proteins are always challenging targets for crystallography, because they need to be separated from their comfortable membrane environment. CXCR4 is no exception, so in order to solve the structure, the PSI team engineered a more cooperative form of the receptor. They clipped one of the intracellular loops of the receptor and inserted an entire molecule of lysozyme. The two-part protein folds correctly, is still active as a receptor, and with some coaxing, forms high-quality crystals for structure solution. To look at these structures in more detail, the JSmol tab below displays an interactive JSmol.

The JSmol tab below displays an interactive JSmol

Nitrile Reductase QueF (PDB entry 3bp1)

This computational model shows two subunits of QueF (in blue and turquoise), with NADPH (magenta) and a nitrile-modified guanine base (green) in the active site groove. The catalytic cysteines are shown with yellow sulfur atoms. Use the buttons to compare the modeled structure of NADPH with the experimentally-observed positions of guanine and pyrophosphate, and to view all of the atoms in the protein.

References

  1. Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066-1071 (2010).

  2. Alkhatib, G. The biology of CCR5 and CXCR4. Curr. Op. HIV AIDS 4, 96-103 (2009).

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