1t84

From Proteopedia

(Difference between revisions)

Current revision

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

Structural highlights

1t84 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

WASP_HUMAN Defects in WAS are the cause of Wiskott-Aldrich syndrome (WAS) [MIM: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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] Defects in WAS are the cause of thrombocytopenia type 1 (THC1) [MIM: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.^[12] ^[13] ^[14] ^[15] ^[16] Defects in WAS are a cause of neutropenia severe congenital X-linked (XLN) [MIM:300299. XLN is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia.^[17]

Function

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.^[18] ^[19] ^[20]

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

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.

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^[21]

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

References

↑ Kwan SP, Hagemann TL, Radtke BE, Blaese RM, Rosen FS. Identification of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4706-10. PMID:7753869
↑ Kolluri R, Shehabeldin A, Peacocke M, Lamhonwah AM, Teichert-Kuliszewska K, Weissman SM, Siminovitch KA. Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. Hum Mol Genet. 1995 Jul;4(7):1119-26. PMID:8528198
↑ Derry JM, Kerns JA, Weinberg KI, Ochs HD, Volpini V, Estivill X, Walker AP, Francke U. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995 Jul;4(7):1127-35. PMID:8528199
↑ Schindelhauer D, Weiss M, Hellebrand H, Golla A, Hergersberg M, Seger R, Belohradsky BH, Meindl A. Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product. Hum Genet. 1996 Jul;98(1):68-76. PMID:8682510
↑ Remold-O'Donnell E, Cooley J, Shcherbina A, Hagemann TL, Kwan SP, Kenney DM, Rosen FS. Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients. J Immunol. 1997 May 1;158(9):4021-5. PMID:9126958
↑ Ariga T, Yamada M, Sakiyama Y. Mutation analysis of five Japanese families with Wiskott-Aldrich syndrome and determination of the family members' carrier status using three different methods. Pediatr Res. 1997 Apr;41(4 Pt 1):535-40. PMID:9098856 doi:10.1203/00006450-199704000-00013
↑ MacCarthy-Morrogh L, Gaspar HB, Wang YC, Katz F, Thompson L, Layton M, Jones AM, Kinnon C. Absence of expression of the Wiskott-Aldrich syndrome protein in peripheral blood cells of Wiskott-Aldrich syndrome patients. Clin Immunol Immunopathol. 1998 Jul;88(1):22-7. PMID:9683546
↑ Facchetti F, Blanzuoli L, Vermi W, Notarangelo LD, Giliani S, Fiorini M, Fasth A, Stewart DM, Nelson DL. Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome. J Pathol. 1998 May;185(1):99-107. PMID:9713366 doi:<99::AID-PATH48>3.0.CO;2-L 10.1002/(SICI)1096-9896(199805)185:1<99::AID-PATH48>3.0.CO;2-L
↑ Parolini O, Ressmann G, Haas OA, Pawlowsky J, Gadner H, Knapp W, Holter W. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med. 1998 Jan 29;338(5):291-5. PMID:9445409 doi:10.1056/NEJM199801293380504
↑ Lemahieu V, Gastier JM, Francke U. Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat. 1999;14(1):54-66. PMID:10447259 doi:<54::AID-HUMU7>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)14:1<54::AID-HUMU7>3.0.CO;2-E
↑ El-Hakeh J, Rosenzweig S, Oleastro M, Basack N, Berozdnik L, Molina F, Rivas EM, Zelazko M, Danielian S. Wiskott-Aldrich syndrome in Argentina: 17 unique, including nine novel, mutations. Hum Mutat. 2002 Feb;19(2):186-7. PMID:11793485 doi:10.1002/humu.9013
↑ Derry JM, Kerns JA, Weinberg KI, Ochs HD, Volpini V, Estivill X, Walker AP, Francke U. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995 Jul;4(7):1127-35. PMID:8528199
↑ Lemahieu V, Gastier JM, Francke U. Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat. 1999;14(1):54-66. PMID:10447259 doi:<54::AID-HUMU7>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)14:1<54::AID-HUMU7>3.0.CO;2-E
↑ Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, Strina D, Patrosso MC, Ramenghi U, Sacco MG, et al.. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet. 1995 Apr;9(4):414-7. PMID:7795648 doi:http://dx.doi.org/10.1038/ng0495-414
↑ Ho LL, Ayling J, Prosser I, Kronenberg H, Iland H, Joshua D. Missense C168T in the Wiskott--Aldrich Syndrome protein gene is a common mutation in X-linked thrombocytopenia. Br J Haematol. 2001 Jan;112(1):76-80. PMID:11167787
↑ Notarangelo LD, Mazza C, Giliani S, D'Aria C, Gandellini F, Ravelli C, Locatelli MG, Nelson DL, Ochs HD, Notarangelo LD. Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood. 2002 Mar 15;99(6):2268-9. PMID:11877312
↑ Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, Verhoef GE, Boogaerts MA, Fryns JP, You D, Rosen MK, Vandenberghe P. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001 Mar;27(3):313-7. PMID:11242115 doi:10.1038/85886
↑ Cory GO, Garg R, Cramer R, Ridley AJ. Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. Wiskott-Aldrich Syndrome protein. J Biol Chem. 2002 Nov 22;277(47):45115-21. Epub 2002 Sep 15. PMID:12235133 doi:10.1074/jbc.M203346200
↑ Chereau D, Kerff F, Graceffa P, Grabarek Z, Langsetmo K, Dominguez R. Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16644-9. Epub 2005 Nov 7. PMID:16275905
↑ Cheng HC, Skehan BM, Campellone KG, Leong JM, Rosen MK. Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U). Nature. 2008 Aug 21;454(7207):1009-13. Epub 2008 Jul 23. PMID:18650809 doi:10.1038/nature07160
↑ Peterson JR, Bickford LC, Morgan D, Kim AS, Ouerfelli O, Kirschner MW, Rosen MK. Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nat Struct Mol Biol. 2004 Aug;11(8):747-55. Epub 2004 Jul 4. PMID:15235593 doi:10.1038/nsmb796

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/1t84"

@@ Line 1: / Line 1: @@
-[[Image:1t84.gif|left|200px]]<br />
-<applet load="1t84" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1t84" />
-'''Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor'''<br />
-==Overview==
+==Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor==
-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.
+<StructureSection load='1t84' size='340' side='right'caption='[[1t84]]' scene=''>
+== Structural highlights ==
+<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>
+</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=WSK:(2S)-1-(3,6-DIBROMO-9H-CARBAZOL-9-YL)-3-(DIMETHYLAMINO)PROPAN-2-OL'>WSK</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=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>
+</table>
+== Disease ==
+[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>
+== Function ==
+[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>
+== 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/t8/1t84_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=1t84 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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.
-==Disease==
+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>
-Known diseases associated with this structure: Neutropenia, severe congenital, X-linked OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]], Thrombocytopenia, X-linked OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]], Thrombocytopenia, X-linked, intermittent OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]], Wiskott-Aldrich syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]]
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-T84 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 WSK as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1T84 OCA].
+</div>
+<div class="pdbe-citations 1t84" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-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://ispc.weizmann.ac.il//pmbin/getpm?pmid=15235593 15235593]
+*[[Wiskott-Aldrich syndrome protein 3D structures|Wiskott-Aldrich syndrome protein 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Bickford, L.C.]]
+[[Category: Bickford LC]]
-[[Category: Kim, A.S.]]
+[[Category: Kim AS]]
-[[Category: Kirschner, M.W.]]
+[[Category: Kirschner MW]]
-[[Category: Morgan, D.]]
+[[Category: Morgan D]]
-[[Category: Ouerfelli, O.]]
+[[Category: Ouerfelli O]]
-[[Category: Peterson, J.R.]]
+[[Category: Peterson JR]]
-[[Category: Rosen, M.K.]]
+[[Category: Rosen MK]]
-[[Category: WSK]]
-[[Category: alpha helix]]
-[[Category: beta-hairpin turn]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:21:54 2007''

1t84

From Proteopedia

Current revision

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

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

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