Evripidis Gavathiotis, Ph.D.
The Gavathiotis laboratory investigates the structure and function of protein interactions to elucidate the molecular mechanisms that regulate cell death and survival signaling pathways and are deregulated in pathological processes such as cancer and cardiovascular disease. The overarching goal of our research is to translate mechanistic insights of protein interactions into novel pharmacologic strategies and discover chemical probes that modulate these interactions for the development of novel therapeutics.
Our research approach is interdisciplinary, at the interface of chemistry and biology, combining techniques in structural biology (NMR and X-ray crystallography), chemical biology, biochemistry, biophysics, cell biology and computer-aided drug design. Projects include medicinal chemistry, proteomics and pharmacology in ex vivo and in vivo animal models through active collaborations.
Structural Biology of Cell Death Mechanisms
Programmed cell death is a genetically controlled physiological process that rids the body of unwanted or malfunctioning cells to maintain the normal development and homeostasis of multicellular organisms. Dysregulation of cell death programs leads to variety of disease conditions and understanding the molecular mechanisms that govern cell death signaling pathways is both fundamentally important and medically relevant. Our focus has been the mitochondrial apoptotic signaling pathway and specifically the protein interaction network of the BCL-2 family of proteins. We have published the first structural analysis of a BH3 death domain in complex with pro-apoptotic BAX, uncovering a new regulatory site on BAX and providing the first glimpse into the trigger mechanism for pro-apoptotic BAX activation. We also revealed the essential role of key structural regions that undergo conformational changes upon BAX activation and enable auto-activation of BAX by a “hit and run” mechanism. Our work, using primarily NMR spectroscopy combined with biochemical, biophysical and cell biology studies, aim to reveal how interactions of the BCL-2 protein family regulate apoptosis and thereby control cellular fate. We are keen to understand critical points of crosstalk between cell death and survival/growth signaling pathways. Therefore, we aim to elucidate the mechanisms of protein-protein interactions and post-translational modifications that regulate apoptotic proteins and define the very determinants that modulate life and death decisions.
Chemical Biology of Cell Death Regulation
We apply high-throughput screening and structure-based drug design, using a combination of computational and experimental techniques, to discover chemical compounds that bind to targets and modulate their function. We aim to identify small molecules that bind to allosteric sites and have increased selectivity. We currently investigate novel targets of the cell death pathway, growth factor signaling pathway and transcription regulators that are highly validated in in vivo
models but are considered challenging or "undruggable". We will use these compounds as chemical probes to dissect signaling pathways and as templates for the development of novel therapeutics. Our broader aim is to establish a methodology for targeting dynamic protein-protein interactions and therefore increase opportunities in the drug discovery process. For example, our discovery of an explicit trigger site on BAX establishes a novel drug target and holds promise to unleash novel therapeutic strategies that switch on or off the apoptotic pathway in diseases of deregulated apoptosis. We have recently published the first small-molecule activator of proapoptotic BAX (BAM7) and demonstrated a new paradigm for pharmacologic induction of apoptosis.
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX Activation is Initiated at a Novel Interaction Site. Nature 2008, 455:1076-1081.
Whelan RS, Konstantinidis K, Wei AC, Chen Y, Reyna DE, Jha S, Yang Y, Calvert JW, Lindsten T, Thompson CB, Crow MT, Gavathiotis E, Dorn GW 2nd, O'Rourke B, Kitsis RN. Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci U S A. 2012, 109:6566-6571.
LaBelle JL, Katz SK, Bird GH, Gavathiotis E, Stewart ML, Lawrence C, Fisher JK, Godes M, Pitter K, Kung AL, Walensky LD. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J. Clin. Invest. 2012, 122:2018-2031.
Gavathiotis E*, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD*. Direct and selective small-molecule activation of proapoptotic BAX. Nature Chem. Bio. 2012, 8:639-645.
Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Opferman JT, Walensky LD. A competitive stapled peptide screen identified a selective small molecule that overcomes MCL-1 dependent leukemia cell survival. Chem & Biol. 2012, 19: 1175-1186.
More Information About Dr. Evripidis Gavathiotis
Gavathiotis Laboratory website
Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.