1YSI

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

1YSI の概要

• エントリーDOI: 10.2210/pdb1ysi/pdb
• 関連するPDBエントリー: 1BXL 1G5J 1LXL 1MAZ 1YSG 1YSN 1YSW 1YSX
• 分子名称: Apoptosis regulator Bcl-X, N-[(4'-FLUORO-1,1'-BIPHENYL-4-YL)CARBONYL]-3-NITRO-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE (2 entities in total)
• 機能のキーワード: complex, apoptosis
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion membrane; Single-pass membrane protein (By similarity): Q07817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21356.53

構造登録者

Oltersdorf, 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. (登録日: 2005-02-08, 公開日: 2005-06-07, 最終更新日: 2024-05-22)

主引用文献

Oltersdorf, 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

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

実験手法

SOLUTION NMR