1ysw

From Proteopedia

(Difference between revisions)

Current revision

Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand

Structural highlights

1ysw is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BCL2_HUMAN Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.

Function

BCL2_HUMAN Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
↑ 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. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677-81. Epub 2005 May 15. PMID:15902208 doi:10.1038/nature03579

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1ysw"

@@ Line 1: / Line 1: @@
 ==Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand==
-<StructureSection load='1ysw' size='340' side='right'caption='[[1ysw]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''>
+<StructureSection load='1ysw' size='340' side='right'caption='[[1ysw]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1ysw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YSW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YSW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1ysw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YSW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YSW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=43B:3-NITRO-N-{4-[2-(2-PHENYLETHYL)-1,3-BENZOTHIAZOL-5-YL]BENZOYL}-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE'>43B</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1g5m|1g5m]], [[1gjh|1gjh]], [[1ysg|1ysg]], [[1ysi|1ysi]], [[1ysx|1ysx]], [[1ysn|1ysn]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=43B:3-NITRO-N-{4-[2-(2-PHENYLETHYL)-1,3-BENZOTHIAZOL-5-YL]BENZOYL}-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE'>43B</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ysw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ysw OCA], [https://pdbe.org/1ysw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ysw RCSB], [https://www.ebi.ac.uk/pdbsum/1ysw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ysw ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN]] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
+[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
 == Function ==
-[[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN]] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).<ref>PMID:18570871</ref>
+[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).<ref>PMID:18570871</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 39: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Armstrong, R C]]
+[[Category: Armstrong RC]]
-[[Category: Augeri, D J]]
+[[Category: Augeri DJ]]
-[[Category: Belli, B A]]
+[[Category: Belli BA]]
-[[Category: Bruncko, M]]
+[[Category: Bruncko M]]
-[[Category: Connor, J M.O]]
+[[Category: Deckwerth TL]]
-[[Category: Deckwerth, T L]]
+[[Category: Dinges J]]
-[[Category: Dinges, J]]
+[[Category: Elmore SW]]
-[[Category: Elmore, S W]]
+[[Category: Fesik SW]]
-[[Category: Fesik, S W]]
+[[Category: Hajduk PJ]]
-[[Category: Hajduk, P J]]
+[[Category: Joseph MK]]
-[[Category: Joseph, M K]]
+[[Category: Kitada S]]
-[[Category: Kitada, S]]
+[[Category: Korsmeyer SJ]]
-[[Category: Korsmeyer, S J]]
+[[Category: Kunzer AR]]
-[[Category: Kunzer, A R]]
+[[Category: Letai A]]
-[[Category: Letai, A]]
+[[Category: Li C]]
-[[Category: Li, C]]
+[[Category: Mitten MJ]]
-[[Category: Mitten, M J]]
+[[Category: Nettesheim DG]]
-[[Category: Nettesheim, D G]]
+[[Category: Ng S]]
-[[Category: Ng, S]]
+[[Category: Nimmer PM]]
-[[Category: Nimmer, P M]]
+[[Category: O'Connor JM]]
-[[Category: Oleksijew, A]]
+[[Category: Oleksijew A]]
-[[Category: Oltersdorf, T]]
+[[Category: Oltersdorf T]]
-[[Category: Petros, A M]]
+[[Category: Petros AM]]
-[[Category: Reed, J C]]
+[[Category: Reed JC]]
-[[Category: Rosenberg, S H]]
+[[Category: Rosenberg SH]]
-[[Category: Shen, W]]
+[[Category: Shen W]]
-[[Category: Shoemaker, A R]]
+[[Category: Shoemaker AR]]
-[[Category: Tahir, S K]]
+[[Category: Tahir SK]]
-[[Category: Thompson, C B]]
+[[Category: Thompson CB]]
-[[Category: Tomaselli, K J]]
+[[Category: Tomaselli KJ]]
-[[Category: Wang, B]]
+[[Category: Wang B]]
-[[Category: Wendt, M D]]
+[[Category: Wendt MD]]
-[[Category: Zhang, H]]
+[[Category: Zhang H]]
-[[Category: Apoptosis]]
-[[Category: Complex]]

1ysw

From Proteopedia

Current revision

Solution structure of the anti-apoptotic protein Bcl-2 complexed with an acyl-sulfonamide-based ligand

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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