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 Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Gold shines through properties of nano biosensors

17.08.2017 | Physics and Astronomy

Greenland ice flow likely to speed up: New data assert glaciers move over sediment, which gets more slippery as it gets wetter

17.08.2017 | Earth Sciences

Mars 2020 mission to use smart methods to seek signs of past life

17.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>