1ysx: Difference between revisions
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'''Solution structure of domain 3 from human serum albumin complexed to an anti-apoptotic ligand directed against Bcl-xL and Bcl-2'''<br /> | '''Solution structure of domain 3 from human serum albumin complexed to an anti-apoptotic ligand directed against Bcl-xL and Bcl-2'''<br /> | ||
==Overview== | ==Overview== | ||
Proteins in the Bcl-2 family are central regulators of programmed cell | 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. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1YSX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 4EB as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 1YSX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=4EB:'>4EB</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YSX OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Armstrong, R | [[Category: Armstrong, R C.]] | ||
[[Category: Augeri, D | [[Category: Augeri, D J.]] | ||
[[Category: Belli, B | [[Category: Belli, B A.]] | ||
[[Category: Bruncko, M.]] | [[Category: Bruncko, M.]] | ||
[[Category: Connor, J | [[Category: Connor, J M.O.]] | ||
[[Category: Deckwerth, T | [[Category: Deckwerth, T L.]] | ||
[[Category: Dinges, J.]] | [[Category: Dinges, J.]] | ||
[[Category: Elmore, S | [[Category: Elmore, S W.]] | ||
[[Category: Fesik, S | [[Category: Fesik, S W.]] | ||
[[Category: Hajduk, P | [[Category: Hajduk, P J.]] | ||
[[Category: Joseph, M | [[Category: Joseph, M K.]] | ||
[[Category: Kitada, S.]] | [[Category: Kitada, S.]] | ||
[[Category: Korsmeyer, S | [[Category: Korsmeyer, S J.]] | ||
[[Category: Kunzer, A | [[Category: Kunzer, A R.]] | ||
[[Category: Letai, A.]] | [[Category: Letai, A.]] | ||
[[Category: Li, C.]] | [[Category: Li, C.]] | ||
[[Category: Mitten, M | [[Category: Mitten, M J.]] | ||
[[Category: Nettesheim, D | [[Category: Nettesheim, D G.]] | ||
[[Category: Ng, S.]] | [[Category: Ng, S.]] | ||
[[Category: Nimmer, P | [[Category: Nimmer, P M.]] | ||
[[Category: Oleksijew, A.]] | [[Category: Oleksijew, A.]] | ||
[[Category: Oltersdorf, T.]] | [[Category: Oltersdorf, T.]] | ||
[[Category: Petros, A | [[Category: Petros, A M.]] | ||
[[Category: Reed, J | [[Category: Reed, J C.]] | ||
[[Category: Rosenberg, S | [[Category: Rosenberg, S H.]] | ||
[[Category: Shen, W.]] | [[Category: Shen, W.]] | ||
[[Category: Shoemaker, A | [[Category: Shoemaker, A R.]] | ||
[[Category: Tahir, S | [[Category: Tahir, S K.]] | ||
[[Category: Thompson, C | [[Category: Thompson, C B.]] | ||
[[Category: Tomaselli, K | [[Category: Tomaselli, K J.]] | ||
[[Category: Wang, B.]] | [[Category: Wang, B.]] | ||
[[Category: Wendt, M | [[Category: Wendt, M D.]] | ||
[[Category: Zhang, H.]] | [[Category: Zhang, H.]] | ||
[[Category: 4EB]] | [[Category: 4EB]] | ||
[[Category: complex]] | [[Category: complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:08:42 2008'' | ||
Revision as of 17:08, 21 February 2008
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Solution structure of domain 3 from human serum albumin complexed to an anti-apoptotic ligand directed against Bcl-xL and Bcl-2
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Analbuminemia OMIM:[103600], Dysalbuminemic hyperthyroxinemia OMIM:[103600], Dysalbuminemic hyperzincemia OMIM:[103600]
About this StructureAbout this Structure
1YSX is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
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
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Single protein
- 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.
- 4EB
- Complex