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| - | [[Image:2f2u.gif|left|200px]]<br /><applet load="2f2u" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2f2u, resolution 2.400Å" /> | |
| - | '''crystal structure of the Rho-kinase kinase domain'''<br /> | |
| | | | |
| - | ==Overview== | + | ==crystal structure of the Rho-kinase kinase domain== |
| - | Rho-kinase is a key regulator of cytoskeletal events and a promising drug, target in the treatment of vascular diseases and neurological disorders., Unlike other protein kinases, Rho-kinase requires both N- and C-terminal, extension segments outside the kinase domain for activity, although the, details of this requirement have been elusive. The crystal structure of an, active Rho-kinase fragment containing the kinase domain and both the, extensions revealed a head-to-head homodimer through the N-terminal, extension forming a helix bundle that structurally integrates the, C-terminal extension. This structural organization enables binding of the, C-terminal hydrophobic motif to the N-terminal lobe, which defines the, correct disposition of helix alphaC that is important for the catalytic, activity. The bound inhibitor fasudil significantly alters the, conformation and, consequently, the mode of interaction with the catalytic, cleft that contains local structural changes. Thus, both kinase and drug, conformational pliability and stability confer selectivity. | + | <StructureSection load='2f2u' size='340' side='right'caption='[[2f2u]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2f2u]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F2U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2F2U 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]] 2.4Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M77:5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE'>M77</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=2f2u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f2u OCA], [https://pdbe.org/2f2u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2f2u RCSB], [https://www.ebi.ac.uk/pdbsum/2f2u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2f2u ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ROCK2_BOVIN ROCK2_BOVIN] Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.<ref>PMID:8641286</ref> <ref>PMID:8702756</ref> <ref>PMID:9565595</ref> <ref>PMID:9456324</ref> <ref>PMID:10209029</ref> <ref>PMID:10873572</ref> <ref>PMID:10818093</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/f2/2f2u_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=2f2u ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurological disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment containing the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix alphaC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity. |
| | | | |
| - | ==About this Structure==
| + | Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil.,Yamaguchi H, Kasa M, Amano M, Kaibuchi K, Hakoshima T Structure. 2006 Mar;14(3):589-600. PMID:16531242<ref>PMID:16531242</ref> |
| - | 2F2U is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with M77 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2F2U OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil., Yamaguchi H, Kasa M, Amano M, Kaibuchi K, Hakoshima T, Structure. 2006 Mar;14(3):589-600. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16531242 16531242]
| + | </div> |
| - | [[Category: Bos taurus]]
| + | <div class="pdbe-citations 2f2u" style="background-color:#fffaf0;"></div> |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Hakoshima, T.]]
| + | |
| - | [[Category: Yamaguchi, H.]]
| + | |
| - | [[Category: M77]]
| + | |
| - | [[Category: enzyme-inhibitor complex]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 10:19:30 2007''
| + | ==See Also== |
| | + | *[[Rho-associated protein kinase 3D structures|Rho-associated protein kinase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Bos taurus]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Hakoshima T]] |
| | + | [[Category: Yamaguchi H]] |
| Structural highlights
Function
ROCK2_BOVIN Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.[1] [2] [3] [4] [5] [6] [7]
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
Rho-kinase is a key regulator of cytoskeletal events and a promising drug target in the treatment of vascular diseases and neurological disorders. Unlike other protein kinases, Rho-kinase requires both N- and C-terminal extension segments outside the kinase domain for activity, although the details of this requirement have been elusive. The crystal structure of an active Rho-kinase fragment containing the kinase domain and both the extensions revealed a head-to-head homodimer through the N-terminal extension forming a helix bundle that structurally integrates the C-terminal extension. This structural organization enables binding of the C-terminal hydrophobic motif to the N-terminal lobe, which defines the correct disposition of helix alphaC that is important for the catalytic activity. The bound inhibitor fasudil significantly alters the conformation and, consequently, the mode of interaction with the catalytic cleft that contains local structural changes. Thus, both kinase and drug conformational pliability and stability confer selectivity.
Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil.,Yamaguchi H, Kasa M, Amano M, Kaibuchi K, Hakoshima T Structure. 2006 Mar;14(3):589-600. PMID:16531242[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 1996 May 1;15(9):2208-16. PMID:8641286
- ↑ Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem. 1996 Aug 23;271(34):20246-9. PMID:8702756
- ↑ Goto H, Kosako H, Tanabe K, Yanagida M, Sakurai M, Amano M, Kaibuchi K, Inagaki M. Phosphorylation of vimentin by Rho-associated kinase at a unique amino-terminal site that is specifically phosphorylated during cytokinesis. J Biol Chem. 1998 May 8;273(19):11728-36. PMID:9565595
- ↑ Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S, Tsukita S. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol. 1998 Feb 9;140(3):647-57. PMID:9456324
- ↑ Fukata Y, Oshiro N, Kinoshita N, Kawano Y, Matsuoka Y, Bennett V, Matsuura Y, Kaibuchi K. Phosphorylation of adducin by Rho-kinase plays a crucial role in cell motility. J Cell Biol. 1999 Apr 19;145(2):347-61. PMID:10209029
- ↑ Kaneko T, Amano M, Maeda A, Goto H, Takahashi K, Ito M, Kaibuchi K. Identification of calponin as a novel substrate of Rho-kinase. Biochem Biophys Res Commun. 2000 Jun 24;273(1):110-6. PMID:10873572 doi:http://dx.doi.org/10.1006/bbrc.2000.2901
- ↑ Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, Amano M, Iwamatsu A, Goshima Y, Kaibuchi K. Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem. 2000 Aug 4;275(31):23973-80. PMID:10818093 doi:http://dx.doi.org/10.1074/jbc.M001032200
- ↑ Yamaguchi H, Kasa M, Amano M, Kaibuchi K, Hakoshima T. Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure. 2006 Mar;14(3):589-600. PMID:16531242 doi:10.1016/j.str.2005.11.024
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