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1YSN

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

Summary for 1YSN
Entry DOI10.2210/pdb1ysn/pdb
Related1BXL 1G5J 1LXL 1MAZ 1YSG 1YSI 1YSW 1YSX
DescriptorApoptosis regulator Bcl-X, 3-NITRO-N-{4-[2-(2-PHENYLETHYL)-1,3-BENZOTHIAZOL-5-YL]BENZOYL}-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE (2 entities in total)
Functional Keywordscomplex, apoptosis
Biological sourceHomo sapiens (human)
Cellular locationMitochondrion membrane; Single-pass membrane protein (By similarity): Q07817
Total number of polymer chains1
Total formula weight21499.76
Authors
Primary citationOltersdorf, T.,Elmore, S.W.,Shoemaker, A.R.,Armstrong, R.C.,Augeri, D.J.,Belli, B.A.,Bruncko, M.,Deckwerth, T.L.,Dinges, J.,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.,O'Connor, J.M.,Oleksijew, A.,Petros, A.M.,Reed, J.C.,Shen, W.,Tahir, S.K.,Thompson, C.B.,Tomaselli, K.J.,Wang, B.,Wendt, M.D.,Zhang, H.,Fesik, S.W.,Rosenberg, S.H.
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Nature, 435:677-681, 2005
Cited by
PubMed Abstract: 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.
PubMed: 15902208
DOI: 10.1038/nature03579
PDB entries with the same primary citation
Experimental method
SOLUTION NMR
Structure validation

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