NIH researchers show how adenosine receptor is ‘switched on,’ shed light on drug interaction

Quickly gaining speed on their path to treating manydisorders in which inflammation plays a key role, researchers from the NationalInstitutes of Health (NIH) have created a three-dimensional depiction of theactivation of a key biological receptor (see video link above, underneath the headline for this story). According to the researchers—whocollaborated with laboratories at the Scripps Research Institute and theUniversity of California, San Diego—showing this type of receptor is "switchedon" will enable scientists to better design molecules for use in experimentaldrugs 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 showthe crystal structure of an adenosine receptor called A2A. Adenosine, which is prevalentthroughout the body, may be important in the function of normal nerve cells, incontrolling cell proliferation and as a signal of inflammation. Of the fouradenosine 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 outsidethe cell and activate inside signal transduction pathways—and ultimately,cellular responses—A2A counteracts inflammation and responds to organs indistress, and understanding how to "switch it on" may enable chemists to betterdesign new drugs for many diseases, says Dr. Kenneth A. Jacobson, chief of theLaboratory of Bioorganic Chemistry in NIH's National Institute of Diabetes andDigestive and Kidney Diseases (NIDDK), and an author on the paper.

According to Jacobson, the NIDDK has been involved in basicresearch on GPCRs, an important class of drug targets, for many years, and thisrecent paper is a continuation of the institute's ongoing efforts to understandthe intricate molecularevents that lead to cellular malfunction and disease. This, researchersbelieve, is the key to developing effective treatments for some of the mostcommon, severe and disabling endocrine and metabolic diseases affectingAmericans today, such as such as diabetes, obesity, hepatitis, inflammatorybowel disease, kidney failure, prostate enlargement and anemia.

In this new study, the team led by Jacobson and hisco-author, Dr. Zhan-Guo Gao, discovered that a previously known agonistmolecule would bind to its receptor target in a way that stabilizes the proteinfor crystallization. Once crystallized, the structure can be seen by bombardingit with X-rays. The agonist solidifies the protein by connecting to multipleparts of the receptor with its molecular arms, initiating the function of theentire structure.

"Untilrecently, we only had an indirect means of understanding the interactionbetween 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 toform good crystals for X-ray structure determination. We showed it is possibleto crystallize a GPCR simply with an agonist—it just has to be the appropriateagonist. With this new structure, we can approach the design of new agonistligands in a more systematic and structure-based manner."

The architecture of the activated receptor enablesscientists to think in more detailed terms about the other half of druginteraction, 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 willexpedite the process of crafting new drugs to treat disease," he says. "Themodeling is best served if it's based on different sources of supportinginformation. That is, one cannot expect to dock a small molecular compoundblindly in a protein without some supportive information, say, an anchor pointwhich may be a key electrostatic interaction or hydrogen bond that one canestablish by mutagenesis. Once you have these supporting information, itgreatly increases the reliability of modeling. That has been our experience."

With this finding, Jacobson and Gao will lead theircolleagues testing this drug-engineering approach with similar molecules theyhave newly synthesized. Several compounds from Jacobson's lab are currently inclinical trials as potential treatments for conditions including chronichepatitis C, psoriasis and rheumatoid arthritis. Can-Fite, an Israeliscience-based biopharmaceutical company, has licensed several compounds fromthe NIH that are in clinical trials in Europe and the United States.

The study, "Structure of an Agonist-Bound Human A2AAdenosine Receptor," was supported by the NIDDK's Intramural Program, whichenables basic scientists and clinicians of diverse skills and expertise tocollaborate on solutions to some of the most difficult issues of human health.

"Discoveries like this, with the potential to lead to futuretreatments in a wide variety of areas, are why NIH funds basic science," saidNIDDK Director Dr. Griffin P. Rodgers in a statement. "By understanding thebody at its smallest components, we can learn how to improve whole-bodyhealth."