Nav: Home

Structure of atypical cancer protein paves way for drug development

January 18, 2017

A team of researchers from Case Western Reserve University School of Medicine has helped uncover the elusive structure of a cancer cell receptor protein that can be leveraged to fight disease progression. Previous studies have showed blocking the receptor can slow tumor growth and metastasis in certain cases. However, the development of drugs (inhibitors) has been slowed by an absence of structural information on this highly unstable membrane protein. Armed with the new study, drug developers can now design molecules that nestle into the receptor's binding sites to modulate its function or outcompete native ligands.

The research team, including Mark Chance PhD, professor and vice dean for research at Case Western Reserve School of Medicine, identified for the first time regions where the receptor interacts with other molecules, including investigational drugs. The findings, published in Nature Communications, provide the first complete structural model for an important class of proteins that sit in the membranes of several types of normal and cancer cells, and are critical mediators of cell-cell communication.

Chance and the team, including investigators at Case Western Reserve University and the University of San Diego, used multiple biochemical and bioinformatics approaches, including novel mass spectrometry techniques, to produce models of "atypical chemokine receptor 3," or ACKR3, alone and in complex with a drug currently in phase 2 trials for treatment of glioblastoma tumors. The researchers also created models of ACKR3 interacting with chemokines, small molecules naturally circulating in the body that control cell movement. The feat required mapping ACKR3 in multiple states, as it dramatically changes shape when bound by these molecular triggers of cell movement.

Said Chance, "ACKR3 is considered an important anti-cancer and immune system target for drug development. ACKR3 can signal cells to grow and move accelerating their cancer potential. By mapping the protein's interactions with known activators as well as drugs that can manipulate function, we can understand its mechanism of action including where the drugs bind and what changes occur in ACKR3 as a result of these interactions."

Chance and his research team used over 100 molecular probes to cover all the static and dynamic regions of ACKR3. The probes helped the team visualize ACKR3 in the laboratory and piece together its structure. "Drug binding results in a conformational change in ACKR3 similar to those of other proteins in its class," said Chance. "We were surprised that the mechanism is so consistent across many types of receptors."

The state-of-the-art techniques used by the team are helping to map other types of cancer-related cell proteins to guide drug development. Information from the study may also allow refinement of compounds currently under development to treat a multitude of cancers.
-end-
Funding for the study was partially provided by National Institutes of Health grants U01 GM094612, U54 GM094618, R01 GM071872, R01 AI118985, R01 AI37113, R21 AI121918, R21 AI122211, GM117424 and P30 EB009998. Study co-author M.G. is supported by a Robertson Foundation/Cancer Research Institute Irvington Fellowship.

For more information about Case Western Reserve University School of Medicine, please visit: http://case.edu/medicine.

Case Western Reserve University

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#514 Arctic Energy (Rebroadcast)
This week we're looking at how alternative energy works in the arctic. We speak to Louie Azzolini and Linda Todd from the Arctic Energy Alliance, a non-profit helping communities reduce their energy usage and transition to more affordable and sustainable forms of energy. And the lessons they're learning along the way can help those of us further south.