Antigen Presentation, Apoptosis/Cell Death, Autoimmunity, Biophysics, Cancer, Computational Biology, Computer Simulation, DNA Repair, Diabetes, Drug Design and Discovery, Enzymology, Gene Regulation, Mathematical and Computational Biology, Membrane Proteins/Channels, Post-Transcriptional Processing, Proteases, Protein Complexes, Protein Folding, Protein Structure/Function, Receptors, Signal Transduction, Structural Biology, T Cells, Theoretical Biophysics, Thermodynamics, Thyroid
Biophysics and Systems Pharmacology [BSP], Cancer Biology [CAB]
BS, Hebrew University
MS, Graduate School of the Hebrew University
PhD, Graduate School of Tel-Aviv University
, Vanderbilt University
Proteolysis by Integral Membrane Proteins
In collaboration with Dr. Iban Ubarretxena we are investigating the origin of selectivity of membrane-bound proteases. The hypothesis is that the secondary structure and dynamics of the helical portion of the substrate is regulating catalysis. To investigate this process we have developed a capability of conducting MD simulations in bilayers as well as in micelles. Our results provide a molecular interpretation of the observed changes in the substrate of GlpG and MCMRJ1, both membrane-bound proteases.
Internal Waters in GPCR and Receptor Signaling
We have developed a theoretical and computational approach to evaluate energetics and dynamics of waters trapped inside proteins. With a visiting student from the University of Barcelona, Jose Carlos Gomez, and Leonardo Pardo we have defined the properties of the network of waters in GPCRs and their ability to allosterically transfer information between two isolated binding pockets in the extra- and intracellular sites. The thermodynamic signature of these waters is of major importance in the regulation of binding and the dynamic properties of the H-bond network are important in modulating biological function. We are applying these theoretical approaches to study the role of waters in GPCR activation, protein-protein interaction and protein-small molecule complexes.
Targeting MAGE Inhibition of Apoptosis: A Therapeutic Approach to Multiple Myeloma
Type I MAGE proteins interact witha RING protein Kap1 (a ubuquitin ligase) through a conserved MAGE homology domain (MHD) that contains two winged helix (WH1 and 2) motifs. X-ray structures show that the WH2 domain exposes the binding site for the RING protein during a conformational change from the free to the bound state. MD simulations of the MAGE-A3 MHD in the closed and open forms demonstrate a hinge region between the WH domains that allows the conformational change to the open form that binds Kap1. Our MD studies also show several structural pockets with unique physicochemical properties that could potentially accommodate small molecules that may prevent the conformational transition of WH2 and arrest the MHD in the closed conformation. In this form MAGE-A3 cannot interact with the RING protein Kap1 and thus induce apoptosis in multiple myeloma cells. We have used the closed form of MAGE-A3 to conduct an in silico screen on large and chemically diverse libraries and discovered at least three small molecules that interact with MAGE-A3 and induce apoptosis of myeloma cells. In collaboration with Dr. Opher Giladi from Oxford, England we have determined the structure of MAGE A3 at 2.07 Å resolution. This structure has been used to conduct MD simulation to determine the binding affinity and the sites of interaction with the small ligands we identified. In collaboration with Hearn Jay Cho we are evaluating the activity of these compounds against multiple myeloma cell lines to determine which ones are suitable leads for further development as MAGE-targeted agents.
Blocking Antigen Presentation in Autoimmunity
The long-term goal of this project is to develop a molecular understanding of peptide presentation by MHC proteins and the molecular mechanisms of autoimmune diseases. In a combined theoretical-experimental collaborative approach, we investigate the interaction of the peptides with MHC proteins responsible for autoimmune thyroid diseases and type I diabetes. The collaboration is between this laboratory and that of Yaron Tomer .
We design small molecule antagonists and specially designed peptides to prevent immunogenic peptide binding to MHC class II proteins. Our hypothesis is that by preventing peptide binding we can inhibit T-cell receptor activation and reduce or prevent the autoimmune response. These molecules may open an opportunity to design new therapeutic approaches to prevent autoimmune thyroid disease, type 1 diabetes as well as other autoimmune diseases. Recently we have demonstrated that at least three small molecules inhibit antigen binding and T-cell stimulation at µM range. We are planning to refine the structure of the lead compounds and use the current discoveries in designing clinical studies on the effectiveness of these inhibitors in suppressing autoimmune thyroid disease.
Miaskiewicz K, Miller J, Ornstein R, Osman R. Molecular dynamics simulations of the effects of ring-saturated thymine lesions on DNA structure. Biopolymers 1995; 35: 113-124.
Laakkonen LJ, Guarnieri F, Perlman JH, Gershengorn MC, Osman R. A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Novel mixed mode Monte Carlo/Stochastic Dynamics simulation of th. Biochemistry 1996; 35: 7651-7663.
Miaskiewicz K, Miller J, Cooney M, Osman R. Computatonal simulations of DNA distortions by a cis,syn-cyclobutance thymine dimer lesion. J Am Chem Soc 1996; 118: 9156-9163.
Laakkonen LJ, Li W, Perlman JH, Guarnieri F, Osman R, Moeller KD, Gershengorn MC. Restricted analogs provide evidence of a biologically active conformation of thyrotropin-releasing hormones. Mol Pharmacol 1996; 49: 1092-1096.
Perlman JH, Colson A-, Wang W, Bence K, Osman R, Gershengorn MC. Interactions between conserved residues in transmembrane helices 1,2, and 7 of the thyrotropin-releasing hormone receptor. J Biol Chem 1997; 272: 11937-11942.
Pasi M, Maddocks JH, Beveridge DL, Bishop TC, Case DA, Cheatham, 3rd TE, Dans PD, Jayaram B, Lankas F, Laughton C, Mitchell J, Osman R, Orozco M, Perez A, Petkeviciute D, Spackova N, Sponer J, Zakrzewska K, Lavery R. muABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.. Nucleic Acids Res 2014; 42(19): 12272-83.
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