New structure of key protein holds clues for better drug design

The scientists working at the Scripps Research Institute (TSRI) have elucidated the molecular structure of  a key protein, which is used extensively in drug design. With this discovery, scientists can now develop to new ways to combat infectious diseases. They have discovered the structure of the protein named A2A adenosine receptor (A2aAR), which is a member of the G-protein-coupled receptor (GPCR) family. Approximately 40 percent of all approved pharmaceutical drugs use this protein as target molecule.

Furthermore, scientists have uncovered the detailed signaling mechanism of the protein A2aAR, helping us understand the inner workings of this proteins. For example, an amino acid of A2aAR acts like a “toggle switch” and controls the signaling processes of 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 protein A2aAR and other molecules of the GPCR family are embedded into plasma membrane of human cells. A normal human body contains more than 800 GPCRs and each protein molecule regulates the metabolic functions of the human body. Scientists have reported that the protein A2aAR is associated with the regulation of blood flow and inflammation. The harmful effects of caffeine are also alleviated by the protein A2aAR. For treating Parkinson’s disease, A2aAR is a relatively new target. Moreover, the protein A2aAR is reported to be a relatively new target in the treatment of cancer.

In recent years, X-ray crystallography has been used to determine the three-dimensional structure of A2aAR protein in previous studies. The X-ray images show that A2aAR protein resembles a chain, and it crisscrosses the cell membrane. An opening is present on the side that faces out of the cell. For signaling associate proteins inside the cell, a section of the GPCR structure emerges out of the membrane and gets associated with drugs.

During inactive and active-like states, an outline of the receptor’s shape was provided by the crystal structure. When A2aAR was combined with new candidate compounds of the pharmaceutical industry, they acted as binding partners; however, 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, strong magnetic fields were used to probe the samples.

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 internal structural changes in the A2aAR proteins.

In this study, researchers investigated the effects of binding drugs with extracellular surface. Changes were observed in the structure of proteins and in the dynamics of the protein surface at an intracellular level. Thus, scientists discovered the mechanism of signal transfer through intracellular pathways. Chemists modified drugs and manipulated the switch to control A2aAR signals.

 

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