|Name||Dr. Vasantha Kumar Machohally Venkateshaiah|
|Organization or Institution||University of South Florida|
|Topic||Biochemistry / Chem Bio.|
NMR Spectroscopy: Insights into protein-ligand interactions
Vasantha Kumar M. V. ; Edvinas Sipavicius ; Radwan E. Noor ; Dimitra Keramisanou and Ioannis Gelis
The University of South Florida, Department of Chemistry
1] Heat shock protein 90α (Hsp90α) is a highly conserved molecular chaperone that plays a crucial role in oncogenesis. It is mainly responsible for the folding, stabilization, and maturation of multiple oncoproteins, which are implicated in cancer progression. Therefore, HSP90α has emerged as an important target in cancer therapeutics and has subsequently become the focus of several drug discovery and development efforts. The studies suggest the majority of Hsp90α N-terminal inhibitors (ATP analogs) showed inefficiency in the suppression of tumor progression, significant cytotoxicity towards noncancer cells, and an inability to proceed within FDA clinical trials. As an alternative, C-terminal Hsp90α inhibitors (Novobiocin analogs) KU596 and KU32 showed the ability to uncouple the unfavorable cytotoxic and cytoprotective outcomes of Hsp90α modulation. Thus they are emerging as a potential drug candidate for oncogenic intervention. NMR spectroscopy offers the Saturation-transfer difference (STD) NMR experiment, which helps to accurately determine weak and strong protein-ligand interactions and their relative affinities or dissociation constant "Kd" of Hsp90α and its C-terminal inhibitors.
2] p38 Mitogen-activated protein kinase (MAPK) is a key signaling molecule which promotes regular cell proliferation and apoptosis. Dysfunction of p38 kinase activity leads to aberrant cell signaling and production of proinflammatory cytokines that are implicated in several types of cancer. Canonical p38α kinase activation is well studied by other biophysical techniques, however, biomolecular NMR spectroscopy will shed more light on the p38α interaction pathway details. With this, we want to assess the importance of the interactions between p38α and Cdc37 and its embroilment within the Hsp90α chaperone cycle.