Structure of a pair of linked CXCR4 molecules (blue and gold) bound by loop-shaped peptide inhibitors (red and magenta). Courtesy of Raymond C. Stevens, the Scripps Research Institute, La Jolla, Calif.
The molecule, CXCR4, is part of a large family of proteins called G-protein coupled receptors (GPCRs). These molecules span the cell’s membrane and transmit signals from the external environment to the cell’s interior. GPCRs help control practically every bodily process, including cell growth, hormone secretion and light perception. Nearly half of all drugs on the market target these receptors.
“Scientists have been studying CXCR4 for years but have only been able to guess at what it looks like,” said NIH Director Francis S. Collins, M.D., Ph.D. “Now that we have its structure, we have a much clearer picture of how this medically important molecule works, opening up entire new areas for drug discovery.”
The researchers, led by Raymond C. Stevens, Ph.D., of the Scripps Research Institute in La Jolla, Calif., report their findings in the Oct. 7, 2010, advance online issue of the journal Science. The study received support from two major NIH initiatives: the structural biology program of the NIH Common Fund and the Protein Structure Initiative (PSI).
While a molecule called CD4 is the primary receptor for HIV, CD4 is not sufficient for the virus to penetrate cells. In 1996, a team of researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) discovered that CXCR4 acts as a co-receptor by helping HIV enter cells.
Normally, CXCR4 helps activate the immune system and stimulate cell movement. But when the signals that activate the receptor aren’t properly regulated, CXCR4 can spur the growth and spread of cancer cells. To date, CXCR4 has been linked to more than 20 types of cancer.
The Scripps Research scientists set out to shed light on how CXCR4 functions by capturing snapshots of the protein by using a structure determination method called X-ray crystallography. To understand how natural molecules might bind and signal through the receptor and to see how potential drugs could interact with it, they examined CXCR4 bound to known inhibitors of its activity.
Model of how HIV latches on to immune cell receptors. (Download the free QuickTime Player to view)
Determining the structure of CXCR4 represented a major challenge because membrane proteins are notoriously tricky to coax into the crystal form required for the X-ray technique. After 3 years of optimizing conditions for producing, stabilizing and crystallizing the molecule, the scientists finally generated five distinct structures of CXCR4.
The structures showed that CXCR4 molecules form closely linked pairs, confirming data from other experiments indicating that pairing plays a role in the proper functioning of the receptor. With this knowledge, scientists can delve into how the duos might regulate CXCR4’s activity and better understand how CXCR4 functions under normal and disease conditions.
The images also showed that CXCR4 is shaped like two white wine glasses touching in a toast, with the inhibitors bound at the sides of the bowls. By detailing these contacts, the researchers said the pictures suggest how to design compounds that regulate CXCR4 activity or block HIV entry into cells. If developed into drugs, such compounds could offer new ways to treat HIV infection or cancer.
“An approach to determining protein structures that was developed with support from the NIH Common Fund and the PSI is now paying huge dividends,” said Jeremy M. Berg, Ph.D., director of the National Institute of General Medical Sciences, which supports the PSI. “It illustrates how technical progress provides a foundation for rapid advances, and it also showcases the benefits of collaborations between structural biologists and scientists working in other fields for addressing fundamentally important problems with tremendous potential for medical applications.”
The research also was supported by NIAID and the National Center for Research Resources, also part of NIH.
To arrange an interview with NIGMS Director Jeremy M. Berg, Ph.D., or Ward Smith, Ph.D., director of the NIGMS Protein Structure Initiative, contact the NIGMS Office of Communications and Public Liaison at 301-496-7301. For more information about the NIGMS Protein Structure Initiative, go to http://www.nigms.nih.gov/Initiatives/PSI/.
NIGMS is a part of NIH that supports basic research to increase our understanding of life processes and lay the foundation for advances in disease diagnosis, treatment and prevention. For more information on the Institute’s research and training programs, see http://www.nigms.nih.gov.
NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
NCRR provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat and prevent a wide range of diseases. NCRR supports all aspects of translational and clinical research, connecting researchers, patients and communities across the nation. For more information, visit www.ncrr.nih.gov.
The NIH Common Fund encourages collaboration and supports a series of exceptionally high impact, trans-NIH programs. The Structural Biology Program is funded through the Common Fund, and managed by the NIH Office of the Director in partnership with the various NIH Institutes, Centers and Offices. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.
The National Institutes of Health (NIH)—The Nation’s Medical Research Agency—includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Reference: Wu B, Chien EYT, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC. Structures of the CXCR4 chemokine receptor in complex with small molecule and cyclic peptide antagonists. Science Express, October 7, 2010.The high-resolution structure sheds light on how the molecule functions and could point to ways to control its activity, potentially locking out HIV and stalling cancer’s spread.