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Study details structure of potential target for HIV and cancer drugs

Date:
October 11, 2010
Source:
NIH/National Institute of General Medical Sciences
Summary:
In a technical tour de force, structural biologists have determined the three-dimensional structure of a molecule involved in HIV infection and in many forms of cancer. 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.

This is a structure of a pair of linked CXCR4 molecules (blue and gold) bound by loop-shaped peptide inhibitors (red and magenta).
Credit: Raymond Stevens, the Scripps Research Institute, La Jolla, Calif.

In a technical tour de force, structural biologists funded by the National Institutes of Health have determined the three-dimensional structure of a molecule involved in HIV infection and in many forms of cancer. 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.

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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.

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 three 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.


Story Source:

The above story is based on materials provided by NIH/National Institute of General Medical Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. Beili Wu, Ellen Y. T. Chien, Clifford D. Mol, Gustavo Fenalti, Wei Liu, Vsevolod Katritch, Ruben Abagyan, Alexei Brooun, Peter Wells, F. Christopher Bi, Damon J. Hamel, Peter Kuhn, Tracy M. Handel, Vadim Cherezov, and Raymond C. Stevens. Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists. Science, 2010; DOI: 10.1126/science.1194396

Cite This Page:

NIH/National Institute of General Medical Sciences. "Study details structure of potential target for HIV and cancer drugs." ScienceDaily. ScienceDaily, 11 October 2010. <www.sciencedaily.com/releases/2010/10/101007141110.htm>.
NIH/National Institute of General Medical Sciences. (2010, October 11). Study details structure of potential target for HIV and cancer drugs. ScienceDaily. Retrieved October 31, 2014 from www.sciencedaily.com/releases/2010/10/101007141110.htm
NIH/National Institute of General Medical Sciences. "Study details structure of potential target for HIV and cancer drugs." ScienceDaily. www.sciencedaily.com/releases/2010/10/101007141110.htm (accessed October 31, 2014).

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