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1YSX

Solution structure of domain 3 from human serum albumin complexed to an anti-apoptotic ligand directed against Bcl-xL and Bcl-2

1YSX の概要
エントリーDOI10.2210/pdb1ysx/pdb
関連するPDBエントリー1YSG 1YSI 1YSN 1YSW
分子名称Serum albumin, 4-({2-[(2,4-DIMETHYLPHENYL)SULFANYL]ETHYL}AMINO)-N-[(4'-FLUORO-1,1'-BIPHENYL-4-YL)CARBONYL]-3-NITROBENZENESULFONAMIDE (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Secreted: P02768
タンパク質・核酸の鎖数1
化学式量合計23265.99
構造登録者
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
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
主引用文献が同じPDBエントリー
実験手法
SOLUTION NMR
構造検証レポート
Validation report summary of 1ysx
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-09に公開中

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