UCSD. US: Researchers at University of California, San Diego Skaggs School of
Pharmacy and Pharmaceutical Sciences and the Bridge Institute at the
University of Southern California report the first crystal structure of
the cellular receptor CXCR4 bound to an immune signaling protein called a
chemokine. The structure, published Jan. 22 in Science,
answers longstanding questions about a molecular interaction that plays
an important role in human development, immune responses, cancer
metastasis and HIV infections.
“This new information could ultimately aid the development of better
small molecular inhibitors of CXCR4-chemokine interactions — inhibitors
that have the potential to block cancer metastasis or viral infections,”
said Tracy M. Handel, PhD, professor of pharmacology at UC San Diego
and senior author of the study.
CXCR4 is a receptor that sits on the outer surface of cells, sticking
out like an antenna. When it receives a message, in the form of
signaling molecules called chemokines, the receptor binds the chemokines
and transmits the message to the inside of the cell. This signal relay
helps cells migrate normally during development and inflammation. But
CXCR4 signaling can also play a role in abnormal cell migration, such as
when cancer cells metastasize. CXCR4 is infamous for another reason:
HIV uses it to bind and infect human immune cells.
Despite its far-reaching consequences, researchers have long lacked
data to show how exactly the CXCR4-chemokine interaction occurs, or even
how many CXCR4 receptors a single chemokine molecule might
simultaneously engage. This is because membrane receptors like CXCR4 are
exceptionally challenging structural targets. The difficulty
dramatically increases when studying such receptors in complexes with
the proteins they bind.
To overcome these experimental challenges, Handel’s team used a novel
approach. They combined computational modeling and a technique known as
disulfide trapping to stabilize the complex. Once stabilized, the
researchers were able to use X-ray crystallography to determine the
CXCR4-chemokine complex’s 3D atomic structure.
This is the first time that a receptor like CXCR4 has been
crystallized with a protein binding partner and the results revealed
several new insights. First, the new crystal structure shows that one
chemokine binds to just one receptor. Additionally, the structure
reveals that the contacts between the receptor and its binding partner
are more extensive than previously thought — it is one very large
contiguous surface of interaction rather than two separate binding
sites.
“The plasticity of the CXCR4 receptor — its ability to bind many
unrelated small molecules, peptides and proteins — is remarkable,” said
Irina Kufareva, PhD, a computational scientist at UC San Diego and
co-corresponding author of the study. “Our understanding of this
plasticity may impact the design of therapeutics with better inhibition
and safety profiles.”
“With more than 800 members, seven-transmembrane receptors like CXCR4
are the largest protein family in the human genome,” added Raymond
Stevens, PhD, provost professor and director of the Bridge Institute at
the University of Southern California and co-corresponding author. “Each
new structure opens up so many doors to understanding different aspects
of human biology, and this time it is about chemokine signaling.”
Study co-authors include Ling Qin, Lauren G. Holden, Yi Zheng,
Chunxia Zhao and Ruben Abagyan, UC San Diego Skaggs School of Pharmacy;
Chong Wang, Gustavo Fenalti, Huixian Wu, Gye Won Han, The Scripps
Research Institute; and Vadim Cherezov, University of Southern
California (previously at The Scripps Research Institute).
This research was made possible by the PSI:Biology program funded by
the National Institute of General Medical Sciences at the National
Institutes of Health (NIH). This research was also funded, in part, by
NIH grants R01GM071872, U01GM094612, R01GM081763, R21AI101687,
U54GM094618, Y1-CO-1020 and Y1-GM-1104, and the Pharmaceutical Research
and Manufacturers of America Foundation.