1YSX

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

Summary for 1YSX

• Entry DOI: 10.2210/pdb1ysx/pdb
• Related: 1YSG 1YSI 1YSN 1YSW
• Descriptor: 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)
• Functional Keywords: complex, apoptosis
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02768
• Total number of polymer chains: 1
• Total formula weight: 23265.99

Authors

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. (deposition date: 2005-02-09, release date: 2005-06-07, Last modification date: 2024-05-22)

Primary citation

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

Experimental method

SOLUTION NMR