1t84

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[[Image:1t84.png|left|200px]]
 
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==Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor==
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<StructureSection load='1t84' size='340' side='right'caption='[[1t84]]' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[1t84]] 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=1T84 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T84 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WSK:(2S)-1-(3,6-DIBROMO-9H-CARBAZOL-9-YL)-3-(DIMETHYLAMINO)PROPAN-2-OL'>WSK</scene></td></tr>
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{{STRUCTURE_1t84| PDB=1t84 | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1t84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t84 OCA], [https://pdbe.org/1t84 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t84 RCSB], [https://www.ebi.ac.uk/pdbsum/1t84 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t84 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/WASP_HUMAN WASP_HUMAN] Defects in WAS are the cause of Wiskott-Aldrich syndrome (WAS) [MIM:[https://omim.org/entry/301000 301000]; also known as eczema-thrombocytopenia-immunodeficiency syndrome. WAS is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10.<ref>PMID:7753869</ref> <ref>PMID:8528198</ref> <ref>PMID:8528199</ref> <ref>PMID:8682510</ref> <ref>PMID:9126958</ref> <ref>PMID:9098856</ref> <ref>PMID:9683546</ref> <ref>PMID:9713366</ref> <ref>PMID:9445409</ref> <ref>PMID:10447259</ref> <ref>PMID:11793485</ref> Defects in WAS are the cause of thrombocytopenia type 1 (THC1) [MIM:[https://omim.org/entry/313900 313900]. Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting.<ref>PMID:8528199</ref> <ref>PMID:10447259</ref> <ref>PMID:7795648</ref> <ref>PMID:11167787</ref> <ref>PMID:11877312</ref> Defects in WAS are a cause of neutropenia severe congenital X-linked (XLN) [MIM:[https://omim.org/entry/300299 300299]. XLN is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia.<ref>PMID:11242115</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/WASP_HUMAN WASP_HUMAN] Effector protein for Rho-type GTPases. Regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria.<ref>PMID:12235133</ref> <ref>PMID:16275905</ref> <ref>PMID:18650809</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/t8/1t84_consurf.spt"</scriptWhenChecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1t84 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Current drug discovery efforts focus primarily on proteins with defined enzymatic or small molecule binding sites. Autoregulatory domains represent attractive alternative targets for small molecule inhibitors because they also occur in noncatalytic proteins and because allosteric inhibitors may avoid specificity problems inherent in active site-directed inhibitors. We report here the identification of wiskostatin, a chemical inhibitor of the neural Wiskott-Aldrich syndrome protein (N-WASP). Wiskostatin interacts with a cleft in the regulatory GTPase-binding domain (GBD) of WASP in the solution structure of the complex. Wiskostatin induces folding of the isolated, unstructured GBD into its autoinhibited conformation, suggesting that wiskostatin functions by stabilizing N-WASP in its autoinhibited state. The use of small molecules to bias conformational equilibria represents a potentially general strategy for chemical inhibition of autoinhibited proteins, even in cases where such sites have not been naturally evolved in a target.
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===Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor===
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Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation.,Peterson JR, Bickford LC, Morgan D, Kim AS, Ouerfelli O, Kirschner MW, Rosen MK Nat Struct Mol Biol. 2004 Aug;11(8):747-55. Epub 2004 Jul 4. PMID:15235593<ref>PMID:15235593</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 1t84" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_15235593}}, adds the Publication Abstract to the page
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*[[Wiskott-Aldrich syndrome protein 3D structures|Wiskott-Aldrich syndrome protein 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 15235593 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_15235593}}
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__TOC__
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</StructureSection>
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==About this Structure==
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1T84 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T84 OCA].
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==Reference==
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Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation., Peterson JR, Bickford LC, Morgan D, Kim AS, Ouerfelli O, Kirschner MW, Rosen MK, Nat Struct Mol Biol. 2004 Aug;11(8):747-55. Epub 2004 Jul 4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15235593 15235593]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Bickford, L C.]]
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[[Category: Bickford LC]]
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[[Category: Kim, A S.]]
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[[Category: Kim AS]]
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[[Category: Kirschner, M W.]]
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[[Category: Kirschner MW]]
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[[Category: Morgan, D.]]
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[[Category: Morgan D]]
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[[Category: Ouerfelli, O.]]
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[[Category: Ouerfelli O]]
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[[Category: Peterson, J R.]]
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[[Category: Peterson JR]]
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[[Category: Rosen, M K.]]
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[[Category: Rosen MK]]
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[[Category: Alpha helix]]
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[[Category: Beta-hairpin turn]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 20:19:15 2008''
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Current revision

Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor

PDB ID 1t84

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