CXCR4 acts as a co-receptor by helping HIV enter cells.
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.
molecules span the cell's membrane. This makes it extremely
difficult to form crystals need to determination the proteins
structure. It took three years of optimizing conditions
to produce, stabilize and crystallize 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.
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."
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
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.
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.
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.
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.
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.
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.
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
also was supported by NIAID and the National Center for Research
Resources, also part of NIH.
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/.
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
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 http://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/.
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 http://www.nih.gov/.
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.