4wot

From Proteopedia

(Difference between revisions)

Current revision

ROCK2 IN COMPLEX WITH 1426382-07-1

Structural highlights

4wot is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.93Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ROCK2_HUMAN 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] ^[8]

Publication Abstract from PubMed

ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort towards identification of ROCK inhibitors, we here report the design, synthesis and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display sub-nanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.

Design, Synthesis and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors.,Boland S, Bourin A, Alen J, Geraets J, Schroeders P, Castermans K, Kindt N, Boumans N, Panitti L, Fransen S, Vanormelingen J, Stassen JM, Leysen D, Defert O J Med Chem. 2015 Apr 21. PMID:25898023^[9]

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

References

↑ Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol. 1999 Nov 29;147(5):1023-38. PMID:10579722
↑ Sebbagh M, Hamelin J, Bertoglio J, Solary E, Breard J. Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med. 2005 Feb 7;201(3):465-71. PMID:15699075 doi:10.1084/jem.20031877
↑ Tanaka T, Nishimura D, Wu RC, Amano M, Iso T, Kedes L, Nishida H, Kaibuchi K, Hamamori Y. Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase. J Biol Chem. 2006 Jun 2;281(22):15320-9. Epub 2006 Mar 30. PMID:16574662 doi:10.1074/jbc.M510954200
↑ Ma Z, Kanai M, Kawamura K, Kaibuchi K, Ye K, Fukasawa K. Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome duplication. Mol Cell Biol. 2006 Dec;26(23):9016-34. Epub 2006 Oct 2. PMID:17015463 doi:10.1128/MCB.01383-06
↑ Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009 Feb 27;104(4):531-40. doi: 10.1161/CIRCRESAHA.108.188524. Epub, 2009 Jan 8. PMID:19131646 doi:10.1161/CIRCRESAHA.108.188524
↑ Lock FE, Hotchin NA. Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One. 2009 Dec 4;4(12):e8190. doi: 10.1371/journal.pone.0008190. PMID:19997641 doi:10.1371/journal.pone.0008190
↑ Wang HF, Takenaka K, Nakanishi A, Miki Y. BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. Cancer Res. 2011 Jan 1;71(1):68-77. doi: 10.1158/0008-5472.CAN-10-0030. Epub 2010, Nov 16. PMID:21084279 doi:10.1158/0008-5472.CAN-10-0030
↑ Herskowitz JH, Seyfried NT, Gearing M, Kahn RA, Peng J, Levey AI, Lah JJ. Rho kinase II phosphorylation of the lipoprotein receptor LR11/SORLA alters amyloid-beta production. J Biol Chem. 2011 Feb 25;286(8):6117-27. doi: 10.1074/jbc.M110.167239. Epub 2010 , Dec 8. PMID:21147781 doi:10.1074/jbc.M110.167239
↑ Boland S, Bourin A, Alen J, Geraets J, Schroeders P, Castermans K, Kindt N, Boumans N, Panitti L, Fransen S, Vanormelingen J, Stassen JM, Leysen D, Defert O. Design, Synthesis and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors. J Med Chem. 2015 Apr 21. PMID:25898023 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00308

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4wot"

@@ Line 1: / Line 1: @@
 ==ROCK2 IN COMPLEX WITH 1426382-07-1==
-<StructureSection load='4wot' size='340' side='right' caption='[[4wot]], [[Resolution|resolution]] 2.93&Aring;' scene=''>
+<StructureSection load='4wot' size='340' side='right'caption='[[4wot]], [[Resolution|resolution]] 2.93&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4wot]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WOT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WOT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4wot]] is a 4 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=4WOT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WOT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3SG:METHYL+3-[({2-(AMINOMETHYL)-5-[(3-FLUOROPYRIDIN-4-YL)CARBAMOYL]BIPHENYL-3-YL}CARBONYL)AMINO]-4-FLUOROBENZOATE'>3SG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.93&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3SG:METHYL+3-[({2-(AMINOMETHYL)-5-[(3-FLUOROPYRIDIN-4-YL)CARBAMOYL]BIPHENYL-3-YL}CARBONYL)AMINO]-4-FLUOROBENZOATE'>3SG</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wot OCA], [http://pdbe.org/4wot PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wot RCSB], [http://www.ebi.ac.uk/pdbsum/4wot PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wot ProSAT]</span></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=4wot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wot OCA], [https://pdbe.org/4wot PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wot RCSB], [https://www.ebi.ac.uk/pdbsum/4wot PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wot ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_HUMAN]] 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:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>
+[https://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_HUMAN] 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:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 ==See Also==
-*[[Rho-associated protein kinase|Rho-associated protein kinase]]
+*[[Rho-associated protein kinase 3D structures|Rho-associated protein kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Homo sapiens]]
-[[Category: Alen, J]]
+[[Category: Large Structures]]
-[[Category: Augustin, M]]
+[[Category: Alen J]]
-[[Category: Boland, S]]
+[[Category: Augustin M]]
-[[Category: Bourin, A]]
+[[Category: Boland S]]
-[[Category: Defert, O]]
+[[Category: Bourin A]]
-[[Category: Krapp, S]]
+[[Category: Defert O]]
-[[Category: Leysen, D]]
+[[Category: Krapp S]]
-[[Category: Transferase]]
+[[Category: Leysen D]]

4wot

From Proteopedia

Current revision

ROCK2 IN COMPLEX WITH 1426382-07-1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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