New structure of key protein holds clues for better drug design

Scientists at The Scripps Research Institute (TSRI) have peered deep into the heart of a key protein used in drug design and discovered dynamic structural features that may lead to new ways to target diseases. The protein, called the A2A adenosine receptor (A2aAR), is a member of the G-protein-coupled receptor (GPCR) family, which are the targets of roughly 40 percent of all approved pharmaceuticals.

The new, more detailed image of A2aAR’s signaling mechanism reveals key parts of its inner workings, including an amino acid that acts like a “toggle switch” to control signaling across the cell membrane. Journal Cell published this path-breaking discovery today. Based on imaging techniques, it can be inferred that shape of proteins changes.

The proteins A2aAR and other GPCRs are embedded into plasma membrane of human cells. In the human body, there are more than 800 GPCRs and each plays a pivotal role in regulating the functions of body. The protein A2aAR performs a pivotal role in regulating blood flow and inflammation. The effects of caffeine will be mediated by the protein A2aAR. For treating Parkinson’s disease, A2aAR is a relatively new target. The protein A2aAR is a relatively new target for cancer treatment.

Scientists used X-ray crystallography, an imaging technique, to determine the three-dimensional structure of A2aAR protein in previous studies. The X-ray images show that A2aAR protein resembles a chain, crisscrossing the cell membrane. The side facing out of the cell has an opening. For signaling associate proteins inside the cell, the region of GPCR structure emerges out of the membrane and interacts with drugs.

During inactive and active-like states, crystal structures provided an outline of the receptor’s shape. When A2aAR was combined with new binding partners, such as pharmaceutical candidates, no motion and changes in cell structure was observed. In this study, researchers realized that they need to establish the molecular mechanism through which A2aAR works in combating diseases. Nuclear magnetic resonance (NMR) spectroscopy was used by researchers for investigation. In this process, the positions of probes in a sample were located with these strong magnetic fields. By using NMR technique, the structure of proteins was determined by scientists. Scientists also investigated the dynamic properties of the solutions at temperatures prevalent in the human body.

The team of researchers visualized the changes in the internal structure of A2aAR proteins. In the new study, researchers investigated the effects of binding drugs with extracellular surface. Changes were observed in the protein structure and dynamics at the intracellular surface. Thus, structural basis of signal transfer were determined. Chemists modified drugs and manipulated the switch to control A2aAR signals.


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