Page 266 - AWSAR 2.0

242 || AWSAR Awarded Popular Science Stories - 2019
rescued by USPs and, hence, it creates extra pool of those proteins leading to accumulation and, finally, tumors.
USPs are 56 in number and USP7 is an attractive therapeutic target due to its involvement in oncogenic pathways (multiple myeloma, colorectal cancer and prostate cancer), metabolic, immune disorders and viral infections. “India’s cancer burden will double in next 20 years and one day it will be ‘cancer capital’” states WHO and GLOBOCAN. As per an ICMR report 2017, ~30,770 cases of multiple myeloma were reported and ~1.1 million lives might end in the next decade by colorectal cancer (Lawrence: Cancer Network, 2018 and American Cancer Society, 2018). Now you can imagine that one single protein can decide the fate of human health. Unfortunately, no drug is available in the market that can inhibit this protein and cure the above-mentioned diseases.
But each coin has two
sides. During the early stage
of my Ph.D., while conducting
a literature survey, one thing
I realized that to prevent this
disease it’s not that simple.
Like a warrior, I equipped
myself with Bioinformatics
tools, softwares, algorithms,
web-servers, knowledge-
based databases to elucidate
all in-sight information of USP7
to design novel, efficient and
potent inhibitors against USP7.
After understanding the in-sight
mechanism of USP7, I, later,
wrote a project on designing
inhibitors against USP7 and submitted to ICMR and, fortunately, ICMR acknowledged it and granted ICMR - SRF fellowship to conduct my research. The research activity was as follows:
USP7 is big 130 kDa-1102 amino acid (aa) protein which has N-terminal (for
substrate recognition), Catalytic domain (CD: performs catalytic activity), Connector helix and 5 UBLs (Ubiquitin like domains) and a 12 aa C-terminal tail. It exists in two forms active and inactive. Active means it can perform its functional activity while inactive means it can cannot.It’s basically because of its catalytic site, composed of Cysteine, Histidine and Aspartate. When Cysteine and Histidine fall apart it stays in inactive state but when they come close it gets active. Most importantly there is some component which is responsible for this equilibrium shift of active/inactive. In order to stop functional activity of USP7, it was crucial to understand this component in depth and its activation process. As a spy, I started working on it and then two research papers derailed my work: One said: USP7’s becomes a badboyonitsown,scientificallyitsownC-term tail activates it, second indicated: Another boy (Ubiquitin) interacts with USP7 and activates
it. This lead to confusion as to which finding was right. So, I performed Molecular Dynamic Simulation to understand at microsecond scale and in real-time what was happening in the protein and I found that Ubiquitin activates USP7 while C-term tail stabilizes its state. My work received attention at the Biophysical Meeting USA (2019), where I presented it with the help of CSIR-Travel Grant and my own institute’s funding.
Next challenge was to identify the binding site of USP7 as without knowing the site and its architecture, the designing of the inhibitor was not possible. With the help of Molecular Docking and MD Simulation, I proposed the binding site of USP7. Later co-crystal of USP7 came that aligned well with my findings. This work also highlighted
Protein folding is just like a developing baby in a mother’s womb and during this folding process if some problem occurs (“misfolding”), it loses its native conformation and resulting
in neurological diseases (for example, Alzheimer’s and Parkinson’s) and hence, protein portrays itself as a bad boy.