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NIH researchers show how adenosine receptor is ‘switched on,’ shed light on drug interaction
by Amy Swinderman  |  Email the author


Quickly gaining speed on their path to treating many disorders in which inflammation plays a key role, researchers from the National Institutes of Health (NIH) have created a three-dimensional depiction of the activation of a key biological receptor (see video link above, underneath the headline for this story). According to the researchers—who collaborated with laboratories at the Scripps Research Institute and the University of California, San Diego—showing this type of receptor is "switched on" will enable scientists to better design molecules for use in experimental drugs to treat disease areas with high unmet medical needs, such as arthritis, respiratory disorders and wound healing.
In a study published in the March 10 issue of Science Express, the researchers show the crystal structure of an adenosine receptor called A2A. Adenosine, which is prevalent throughout the body, may be important in the function of normal nerve cells, in controlling cell proliferation and as a signal of inflammation. Of the four adenosine receptors which detect local changes in adenosine concentration—A1, A2A, A2B and A3—A2A is used to sense excessive tissue inflammation.  
As a member of the G protein-coupled receptor (GPCR) family, a large protein group of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways—and ultimately, cellular responses—A2A counteracts inflammation and responds to organs in distress, and understanding how to "switch it on" may enable chemists to better design new drugs for many diseases, says Dr. Kenneth A. Jacobson, chief of the Laboratory of Bioorganic Chemistry in NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and an author on the paper.
According to Jacobson, the NIDDK has been involved in basic research on GPCRs, an important class of drug targets, for many years, and this recent paper is a continuation of the institute's ongoing efforts to understand the intricate molecular events that lead to cellular malfunction and disease. This, researchers believe, is the key to developing effective treatments for some of the most common, severe and disabling endocrine and metabolic diseases affecting Americans today, such as such as diabetes, obesity, hepatitis, inflammatory bowel disease, kidney failure, prostate enlargement and anemia.
In this new study, the team led by Jacobson and his co-author, Dr. Zhan-Guo Gao, discovered that a previously known agonist molecule would bind to its receptor target in a way that stabilizes the protein for crystallization. Once crystallized, the structure can be seen by bombarding it with X-rays. The agonist solidifies the protein by connecting to multiple parts of the receptor with its molecular arms, initiating the function of the entire structure.
"Until recently, we only had an indirect means of understanding the interaction between the drug and its protein target," Jacobson says. "Prior to our study, it was thought that agonist-bound structures would be too unstable or wobbly to form good crystals for X-ray structure determination. We showed it is possible to crystallize a GPCR simply with an agonist—it just has to be the appropriate agonist. With this new structure, we can approach the design of new agonist ligands in a more systematic and structure-based manner."
The architecture of the activated receptor enables scientists to think in more detailed terms about the other half of drug interaction, Jacobson says—a paradigm shift discussed in his previous papers, which met with some skepticism in the research community.  
"We hope that we're on the verge of a revolution that will expedite the process of crafting new drugs to treat disease," he says. "The modeling is best served if it's based on different sources of supporting information. That is, one cannot expect to dock a small molecular compound blindly in a protein without some supportive information, say, an anchor point which may be a key electrostatic interaction or hydrogen bond that one can establish by mutagenesis. Once you have these supporting information, it greatly increases the reliability of modeling. That has been our experience."  
With this finding, Jacobson and Gao will lead their colleagues testing this drug-engineering approach with similar molecules they have newly synthesized. Several compounds from Jacobson's lab are currently in clinical trials as potential treatments for conditions including chronic hepatitis C, psoriasis and rheumatoid arthritis. Can-Fite, an Israeli science-based biopharmaceutical company, has licensed several compounds from the NIH that are in clinical trials in Europe and the United States.
The study, "Structure of an Agonist-Bound Human A2A Adenosine Receptor," was supported by the NIDDK's Intramural Program, which enables basic scientists and clinicians of diverse skills and expertise to collaborate on solutions to some of the most difficult issues of human health.
"Discoveries like this, with the potential to lead to future treatments in a wide variety of areas, are why NIH funds basic science," said NIDDK Director Dr. Griffin P. Rodgers in a statement. "By understanding the body at its smallest components, we can learn how to improve whole-body health."
Code: E04111101



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