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Determination of virus and enzyme structures pave way for drug development

Prof. M. R. N. Murthy from the Molecular Biophysics Unit, IISc has achieved what no other lab in India has been able to so far: by determining the complete structures of not one, but two plant viruses. Less than a dozen labs worldwide have been able to determine the structure of viruses. Determination of the structure of viruses has numerous prospects in the field of vaccine development, drug delivery and imaging. Prof. Murthy was recently awarded the Sir M. Visvesvaraya State Award for Senior Scientists by Karnataka State Council for Science and Technology.

Prof. Murthy’s lab has determined the structures of two plant-viruses. This means, they have determined the three-dimensional structure of the proteins that make up the virus coat or capsid that hosts and protects the viral genome and the pattern of arrangement of the protein subunits on the viral capsids. This was achieved using a technique called X-Ray Diffraction. The structure thus obtained has numerous uses, for studying diseases and their potential treatment methods.

“It was a much harder time back then”, Prof. Murthy says, thinking back to the early days of his discovery when computers were large in size but very limited in terms of memory storage and computational speed. “The computing facilities we have today were not available and I develop every computer program required for structure determination myself.”

It was observed that expression of sesbania mosaic virus messenger RNA in E. coli cells  results in the assembly of the expressed viral coat protein  into virus like particles (VLPs). Murthy has determined the structures of several deletion and site specific mutants of the virus. The structures determined include the so called T=3 icosahedrally symmetric particles with a diameter of 30 nm and T=1 particles consisting of 60 subunits and a diameter of 20 nm. These are nano-particles with potential medical and diagnostic applications. The smaller T=1 particles with 60 subunits are formed by N-terminal deletion mutants of sesbania mosaic virus. coat protein It was also possible to disrupt the assembly of sesbania mosaic virus completely by a suitable site specific mutation. The structure of a dimeric unit of sesbania mosaic virus coat protein obtained by disrupting the assembly has also been elucidated. These studies reveal the intricate molecular mechanisms that lie behind assembly of highly symmetric protein capsids.

These VLPs can be used as a drug delivery system. We can essentially “stitch” a peptide onto the VLP surface, and the VLP can target a particular site in the body. For example, we can stitch a peptide on it so that it is delivered to the liver cells. Inside the cage of this VLP, we can pack the cargo – in this case, a drug – that we want to deliver to the liver cells.  This is a much more effective alternative to loading the entire body with medicines to treat organ-specific conditions.

The work at the lab is could also be used for medical imaging. In this case, a dye/label can be loaded instead of the drug into the capsid or attached to the capsid. It will bind to the target site and show up on imaging.

Additionally, the lab has elucidated the three-Dimensional structures of many enzymes from parasitic microorganisms like Plasmodium falciparum, which causes malaria, and Mycobacterium tuberculosis, which causes tuberculosis. They have also determined the structures of proteins necessary for maintaining the life cycle of Salmonella typhimurium (that causes typhoid). Proteins are synthesized in cells as linear polypeptide chains. Murthy's lab has also determined protein structures that reveal the intricate ways in which proteins fold and attain their three-dimensional structure. the knowledge about the structures of proteins and enzymes of parasitic organisms can help in the development of small organic molecules that inhibit the function of these proteins and thus could act as inhibitors of microbial growth.

Prof. Murthy is actively involved in developing science education throughout the country. “Science is exciting. There is an exciting story before every discovery, great or small.” He believes that every student of science needs to know these stories and feel excited to develop an interest in science. Through his educational programs he has advocated that in both urban areas and educationally backward rural districts. He believes, “Even if you can’t transform society, but you can at least light a few lamps along the way, and that is a very satisfying profession.”

He gives us a final piece of closing advice “Ask yourself- are you as excited today as you were when you first started?”

About the Lab

Dr. M.R.N. Murthy is a Professor at the Molecular Biophysics Unit, Indian Institute of Science, Bangalore.


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