Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Pictured together for the first time: A chemokine and its receptor

23.01.2015

Researchers capture 3-D structure of a molecular interaction that influences cancer, inflammation and HIV infection

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.


The newly solved structure of the CXCR4 receptor (black) in complex with a chemokine (purple surface). The background shows cell migration, a process driven by chemokines interacting with receptors on cell surfaces.

Credit: Katya Kadyshevskaya, USC

"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.

Media Contact

Heather Buschman
hbuschman@ucsd.edu
619-543-6163

 @UCSanDiego

http://www.ucsd.edu 

Heather Buschman | EurekAlert!

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>