Zachariah H. Foda
B.A. Dartmount College, 2009
Ph.D. Stony Brook University, 2015
8th Year MSTP
4th Year Medical Student
Advisor: Markus Seeliger, PhD
Department: Pharmacological Sciences, Stony Brook Univ.
Graduate Program: Molecular & Cellular Biology
Title: Mechanism of allosteric signal integration in Src tyrosine kinase
Abstract:
Dysregulated kinase activity underlies many features of cellular pathogenesis, including self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, sustainment of angiogenesis, and tissue invasion and metastasis. The high sequence and structural conservation of the protein kinase catalytic domain creates a challenge for developing specific inhibitors. Part of the mechanism through which protein kinases achieve precise regulation, though, involves integration of many inter-and intramolecular signals via sites that are considerably less well conserved in sequence and function. These non-conserved mechanisms of regulation therefore provide the opportunity for more precise therapeutic targeting, for example, through the development of allosteric inhibitors based on high-affinity and high-specificity ligands. However, it is challenging to identify such allosteric sites in detail. Recently, our collaborators identified a previously unknown allosteric network of amino acids that spans the length of the kinase and may thus facilitate integration of allosteric signals into the regulation of protein kinase catalytic domain activity. My work experimentally probes the allosteric network and identify ligands that stabilize a predicted allosteric pocket. The findings from this work will deepen our understanding of the fundamental regulatory mechanisms for this important class of drug targets and potentially open the way to the development of more specific therapeutics.
Publication(s):
(pre-MSTP publications indicated with an *)
*Foda Z. H., Y. Shan, E.T. Kim, D.E. Shaw, M.A. (Seeliger 2014). “A dynamically coupled allosteric network underlies binding cooperativity in Src kinase” Nature Communications in press
*Foda, Z. H. and M. A. Seeliger (2014). "Kinase inhibitors: An allosteric add-on." Nat Chem Biol 10(10): 796-797.
*Maianti, J. P., A. McFedries, Z. H. Foda, R. E. Kleiner, X. Q. Du, M. A. Leissring, W. J. Tang, M. J. Charron, M. A. Seeliger, A. Saghatelian and D. R. Liu (2014). "Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones." Nature 511(7507): 94-98.
