7qhg

From Proteopedia

(Difference between revisions)

Revision as of 07:45, 11 January 2023

LIM domain kinase 2 (LIMK2) in complex with TH-470

Structural highlights

7qhg is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LIMK2_HUMAN Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.^[1] ^[2]

Publication Abstract from PubMed

LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 (LIMKi3; type I), 48 (TH470; type II), and 15 (TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15. In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.

Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes.,Hanke T, Mathea S, Woortman J, Salah E, Berger BT, Tumber A, Kashima R, Hata A, Kuster B, Muller S, Knapp S J Med Chem. 2022 Oct 13;65(19):13264-13287. doi: 10.1021/acs.jmedchem.2c01106. , Epub 2022 Sep 22. PMID:36136092^[3]

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

References

↑ Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999 Aug 6;285(5429):895-8. PMID:10436159
↑ Sumi T, Matsumoto K, Nakamura T. Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. J Biol Chem. 2001 Jan 5;276(1):670-6. PMID:11018042 doi:10.1074/jbc.M007074200
↑ Hanke T, Mathea S, Woortman J, Salah E, Berger BT, Tumber A, Kashima R, Hata A, Kuster B, Muller S, Knapp S. Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes. J Med Chem. 2022 Oct 13;65(19):13264-13287. doi: 10.1021/acs.jmedchem.2c01106. , Epub 2022 Sep 22. PMID:36136092 doi:http://dx.doi.org/10.1021/acs.jmedchem.2c01106

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7qhg"

@@ Line 1: / Line 1: @@
 ==LIM domain kinase 2 (LIMK2) in complex with TH-470==
-<StructureSection load='7qhg' size='340' side='right'caption='[[7qhg]]' scene=''>
+<StructureSection load='7qhg' size='340' side='right'caption='[[7qhg]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QHG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QHG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7qhg]] 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=7QHG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QHG FirstGlance]. <br>
-</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=7qhg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qhg OCA], [https://pdbe.org/7qhg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qhg RCSB], [https://www.ebi.ac.uk/pdbsum/7qhg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qhg ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=T3B:2-(2-methylpropanoylamino)-~{N}-[2-[(phenylmethyl)-[4-(phenylsulfamoyl)phenyl]carbonyl-amino]ethyl]-1,3-thiazole-5-carboxamide'>T3B</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=7qhg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qhg OCA], [https://pdbe.org/7qhg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qhg RCSB], [https://www.ebi.ac.uk/pdbsum/7qhg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qhg ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/LIMK2_HUMAN LIMK2_HUMAN] Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.<ref>PMID:10436159</ref> <ref>PMID:11018042</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 (LIMKi3; type I), 48 (TH470; type II), and 15 (TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15. In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.
+Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes.,Hanke T, Mathea S, Woortman J, Salah E, Berger BT, Tumber A, Kashima R, Hata A, Kuster B, Muller S, Knapp S J Med Chem. 2022 Oct 13;65(19):13264-13287. doi: 10.1021/acs.jmedchem.2c01106. , Epub 2022 Sep 22. PMID:36136092<ref>PMID:36136092</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7qhg" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Hanke T]]

7qhg

From Proteopedia

Revision as of 07:45, 11 January 2023

LIM domain kinase 2 (LIMK2) in complex with TH-470

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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