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== | |||
<StructureSection load='1ysx' size='340' side='right'caption='[[1ysx]]' scene=''> | |||
| | == Structural highlights == | ||
| | <table><tr><td colspan='2'>[[1ysx]] 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=1YSX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YSX FirstGlance]. <br> | ||
</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4EB:4-({2-[(2,4-DIMETHYLPHENYL)SULFANYL]ETHYL}AMINO)-N-[(4-FLUORO-1,1-BIPHENYL-4-YL)CARBONYL]-3-NITROBENZENESULFONAMIDE'>4EB</scene></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=1ysx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ysx OCA], [https://pdbe.org/1ysx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ysx RCSB], [https://www.ebi.ac.uk/pdbsum/1ysx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ysx ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ALBU_HUMAN ALBU_HUMAN] Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:[https://omim.org/entry/103600 103600]. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.<ref>PMID:8048949</ref> <ref>PMID:7852505</ref> <ref>PMID:9329347</ref> <ref>PMID:9589637</ref> | |||
== Function == | |||
== | [https://www.uniprot.org/uniprot/ALBU_HUMAN ALBU_HUMAN] Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.<ref>PMID:19021548</ref> | ||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ys/1ysx_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ysx ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== 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. | 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<ref>PMID:15902208</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1ysx" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Albumin 3D structures|Albumin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Armstrong | [[Category: Armstrong RC]] | ||
[[Category: Augeri | [[Category: Augeri DJ]] | ||
[[Category: Belli | [[Category: Belli BA]] | ||
[[Category: Bruncko | [[Category: Bruncko M]] | ||
[[Category: Deckwerth TL]] | |||
[[Category: Deckwerth | [[Category: Dinges J]] | ||
[[Category: Dinges | [[Category: Elmore SW]] | ||
[[Category: Elmore | [[Category: Fesik SW]] | ||
[[Category: Fesik | [[Category: Hajduk PJ]] | ||
[[Category: Hajduk | [[Category: Joseph MK]] | ||
[[Category: Joseph | [[Category: Kitada S]] | ||
[[Category: Kitada | [[Category: Korsmeyer SJ]] | ||
[[Category: Korsmeyer | [[Category: Kunzer AR]] | ||
[[Category: Kunzer | [[Category: Letai A]] | ||
[[Category: Letai | [[Category: Li C]] | ||
[[Category: Li | [[Category: Mitten MJ]] | ||
[[Category: Mitten | [[Category: Nettesheim DG]] | ||
[[Category: Nettesheim | [[Category: Ng S]] | ||
[[Category: Ng | [[Category: Nimmer PM]] | ||
[[Category: Nimmer | [[Category: O'Connor JM]] | ||
[[Category: Oleksijew | [[Category: Oleksijew A]] | ||
[[Category: Oltersdorf | [[Category: Oltersdorf T]] | ||
[[Category: Petros | [[Category: Petros AM]] | ||
[[Category: Reed | [[Category: Reed JC]] | ||
[[Category: Rosenberg | [[Category: Rosenberg SH]] | ||
[[Category: Shen | [[Category: Shen W]] | ||
[[Category: Shoemaker | [[Category: Shoemaker AR]] | ||
[[Category: Tahir | [[Category: Tahir SK]] | ||
[[Category: Thompson | [[Category: Thompson CB]] | ||
[[Category: Tomaselli | [[Category: Tomaselli KJ]] | ||
[[Category: Wang | [[Category: Wang B]] | ||
[[Category: Wendt | [[Category: Wendt MD]] | ||
[[Category: Zhang | [[Category: Zhang H]] | ||