1ysw

From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 1ysw Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Proteins in the Bcl-2 family are central regulators of programmed cell, death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are, overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with, chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase, sensitivity to anticancer drugs and enhance in vivo survival. The, development of inhibitors of these proteins as potential anti-cancer, therapeutics has been previously explored, but obtaining potent, small-molecule inhibitors has proved difficult owing to the necessity of, targeting a protein-protein interaction. Here, using nuclear magnetic, resonance (NMR)-based screening, parallel synthesis and structure-based, design, we have discovered ABT-737, a small-molecule inhibitor of the, anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to, three orders of magnitude more potent than previously reported compounds., Mechanistic studies reveal that ABT-737 does not directly initiate the, apoptotic process, but enhances the effects of death signals, displaying, synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737, exhibits single-agent-mechanism-based killing of cells from lymphoma and, small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of, established tumours, and produces cures in a high percentage of the mice.

Disease

Known disease associated with this structure: Leukemia/lymphoma, B-cell OMIM:[151430]

About this Structure

1YSW is a Single protein structure of sequence from Homo sapiens with 43B as ligand. Full crystallographic information is available from OCA.

Reference

An inhibitor of Bcl-2 family proteins induces regression of solid tumours., Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Nature. 2005 Jun 2;435(7042):677-81. Epub 2005 May 15. PMID:15902208

Page seeded by OCA on Mon Nov 12 20:24:17 2007