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 Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo

nachricht Full of hot air and proud of it
18.04.2018 | University of Pittsburgh

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

Im Focus: The Future of Ultrafast Solid-State Physics

In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.

Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Diamond-like carbon is formed differently to what was believed -- machine learning enables development of new model

19.04.2018 | Materials Sciences

Electromagnetic wizardry: Wireless power transfer enhanced by backward signal

19.04.2018 | Physics and Astronomy

Ultrafast electron oscillation and dephasing monitored by attosecond light source

19.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>