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1ysw
From Proteopedia
| 1ysw, 1 NMR models () | |||||||||
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| Gene: | BCL2 (Homo sapiens) | ||||||||
| Related: | 1g5m, 1gjh, 1ysg, 1ysi, 1ysx, 1ysn | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand
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.
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Disease
Known disease associated with this structure: Leukemia/lymphoma, B-cell OMIM:[151430]
About this Structure
1YSW is a 1 chain structure of sequence from Homo sapiens. Full experimental information is available from OCA.
Reference
- 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. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677-81. Epub 2005 May 15. PMID:15902208 doi:10.1038/nature03579
Page seeded by OCA on Wed Nov 18 18:21:10 2009
Categories: Homo sapiens | Armstrong, R C. | Augeri, D J. | Belli, B A. | Bruncko, M. | Connor, J M.O. | Deckwerth, T L. | Dinges, J. | Elmore, S W. | Fesik, S W. | Hajduk, P J. | Joseph, M K. | Kitada, S. | Korsmeyer, S J. | Kunzer, A R. | Letai, A. | Li, C. | Mitten, M J. | Nettesheim, D G. | Ng, S. | Nimmer, P M. | Oleksijew, A. | Oltersdorf, T. | Petros, A M. | Reed, J C. | Rosenberg, S H. | Shen, W. | Shoemaker, A R. | Tahir, S K. | Thompson, C B. | Tomaselli, K J. | Wang, B. | Wendt, M D. | Zhang, H. | Apoptosis | Complex
