2clq: Difference between revisions

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-[[Image:2clq.gif|left|200px]]<br />
-<applet load="2clq" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2clq, resolution 2.30&Aring;" />
-'''STRUCTURE OF MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5'''<br />
-==Overview==
+==Structure of mitogen-activated protein kinase kinase kinase 5==
-Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in, stress and immune response and has been linked to the development of, several diseases. Here, we present the structure of the human ASK1, catalytic domain in complex with staurosporine. Analytical, ultracentrifugation (AUC) and crystallographic analysis showed that ASK1, forms a tight dimer (K(d) approximately 0.2 muM) interacting in a, head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ, from known ASK1 phosphorylation sites but correspond well to, autophosphorylation sites identified by mass spectrometry. Reporter gene, assays showed that all three identified in vitro autophosphorylation sites, (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed, mutants showed catalytic activities similar to wild-type ASK1, suggesting, a regulatory mechanism independent of ASK1 kinase activity. The determined, high-resolution structure of ASK1 and identified ATP mimetic inhibitors, will provide a first starting point for the further development of, selective inhibitors.
+<StructureSection load='2clq' size='340' side='right'caption='[[2clq]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2clq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CLQ FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=STU:STAUROSPORINE'>STU</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=2clq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2clq OCA], [https://pdbe.org/2clq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2clq RCSB], [https://www.ebi.ac.uk/pdbsum/2clq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2clq ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/M3K5_HUMAN M3K5_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).<ref>PMID:8940179</ref> <ref>PMID:8974401</ref> <ref>PMID:9564042</ref> <ref>PMID:9774977</ref> <ref>PMID:10411906</ref> <ref>PMID:10849426</ref> <ref>PMID:10688666</ref> <ref>PMID:11689443</ref> <ref>PMID:11029458</ref> <ref>PMID:11154276</ref> <ref>PMID:14749717</ref> <ref>PMID:11920685</ref> <ref>PMID:12697749</ref> <ref>PMID:15023544</ref> <ref>PMID:14688258</ref> <ref>PMID:16129676</ref> <ref>PMID:17220297</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/cl/2clq_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=2clq ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-CLQ 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 STU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] Structure known Active Sites: AC1 and AC2. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CLQ OCA].
+*[[Mitogen-activated protein kinase kinase kinase|Mitogen-activated protein kinase kinase kinase]]
+== References ==
-==Reference==
+<references/>
-Structural and Functional Characterization of the Human Protein Kinase ASK1., Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Muller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S, Structure. 2007 Oct;15(10):1215-26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17937911 17937911]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Mitogen-activated protein kinase kinase kinase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Arrowsmith C]]
-[[Category: Arrowsmith, C.]]
+[[Category: Bunkoczi G]]
-[[Category: Bunkoczi, G.]]
+[[Category: Edwards A]]
-[[Category: Delft, F.Von.]]
+[[Category: Fedorov O]]
-[[Category: Edwards, A.]]
+[[Category: Gileadi O]]
-[[Category: Fedorov, O.]]
+[[Category: Knapp S]]
-[[Category: Gileadi, O.]]
+[[Category: Pike A]]
-[[Category: Knapp, S.]]
+[[Category: Salah E]]
-[[Category: Pike, A.]]
+[[Category: Sundstrom M]]
-[[Category: Salah, E.]]
+[[Category: Weigelt J]]
-[[Category: Sundstrom, M.]]
+[[Category: Von Delft F]]
-[[Category: Weigelt, J.]]
-[[Category: STU]]
-[[Category: apoptosis]]
-[[Category: atp-binding]]
-[[Category: kinase]]
-[[Category: magnesium]]
-[[Category: map kinase]]
-[[Category: metal-binding]]
-[[Category: nucleotide-binding]]
-[[Category: phosphorylation]]
-[[Category: protein kinase]]
-[[Category: serine/threonine-protein kinase]]
-[[Category: transferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:16:56 2007''