and leverage these findings to further refine approaches for the prospective development of small molecule degraders. www.vbprofiles.com is now www.topionetworks.com.
The Ubiquitin Proteasome System (UPS) is involved in virtually any cellular process and frequently implicated in human pathologies. Ubiquitin, through the action of a three-enzyme cascade (E1, E2 and E3), becomes attached to substrate proteins. While the process of ubiquitin transfer is well understood, the biological function and molecular mechanisms of the majority of ubiquitin ligases remain obscure. The structure established CRBN as the CRL4, substrate receptor, which enantioselectively binds thalidomide and its analogues, lenalidomide and pomalidomide. Cavadini, S, Fischer, ES, Bunker, R.D, Potenza, A, Gondichatnahalli, ML, Goldie, KN, Mohamed, WI, Faty, M, Petzold, G, Beckwith, REJ, Tichkule, R, Hassiepen, U, Abdulrahman, W., Pantelic, R.S., Matsumoto, S., Sugasawa, K., Stahlberg, H, Thomä, NH., Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Our findings thus, provide a molecular mechanism for thalidomide action that involves inhibition of CRL4CRBN-mediated ubiquitination of endogenous substrates, while simultaneously acting as agonist on neo-substrates such as Ikaros transcription factors. In particular, we are interested in protein complexes and pathways that contribute to the control of gene expression and are frequently associated with human disease and cancer. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature Chemical Biology (in press). Curated profile of Eric Fischer, Principal Investigator, Dana-Farber Cancer Institute including career history, news and intelligence, portfolio companies and investments. 2020-01-12T23:38:05.000Z. The Ubiquitin Proteasome System (UPS) is involved in virtually any cellular process and frequently implicated in human pathologies.
The posttranslational modification with ubiquitin can serve a multitude of functions depending on the type and length of the ubiquitin chain attached to the substrate, including the control of protein expression.
49-53. Plasticity of inter-protein contacts confers selectivity in ligand induced protein degradation. Thomä, N.H., Structural basis of Lenalidomide induced Ck1a degradation by the CRL4. Nature 2014 vol. ubiquitin ligase, illustrates the general approach. Crystal structure of the human COP9 Signalosome. We successfully determined the structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. Department of Biological Chemistry and Molecular Pharmacology Dana Farber Cancer Institute 450 Brookline Avenue (LC4312) Boston, MA 02215 Tel: 617-582-9281 Email: email@example.com Visit my lab page here. Blood. in molecular biology and M.Sc. We also develop computational methods to better understand and predict the molecular interations that comprise the activity of small molecule degraders. Epub 2018 Jul 24. We successfully determined the structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. Using multi-disciplinary chemical biology (including X-ray crystallography, cryo-EM, proteomics, biochemistry and chemical synthesis), we define the mechanism of drugs such as thalidomide, lenalidomide, indisulam, etc. Ubiquitin, through the action of a three-enzyme cascade (E1, …
Fischer, ES, Böhm, K, Lydeard, JR, Yang, H, Stadler, MB, Cavadini, S, Nagel, J, Acker, V, Tichkule, R, Forrester, WC, Schirle, M, Hassiepen, U, Ottl, J, Hild, M, Beckwidth, REJ, Harper, JW, Jenkins, JL, Thomä, NH.