7QHG
LIM domain kinase 2 (LIMK2) in complex with TH-470
Summary for 7QHG
| Entry DOI | 10.2210/pdb7qhg/pdb |
| Descriptor | LIM domain kinase 2, 2-(2-methylpropanoylamino)-~{N}-[2-[(phenylmethyl)-[4-(phenylsulfamoyl)phenyl]carbonyl-amino]ethyl]-1,3-thiazole-5-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | kinase, type-2 inhibitor, actin dynamics, cfl-1, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 71121.21 |
| Authors | Mathea, S.,Salah, E.,Hanke, T.,Knapp, S. (deposition date: 2021-12-12, release date: 2021-12-22, Last modification date: 2024-01-31) |
| Primary citation | Hanke, T.,Mathea, S.,Woortman, J.,Salah, E.,Berger, B.T.,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., 65:13264-13287, 2022 Cited by PubMed Abstract: 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 (; type I), (; type II), and (; 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 . In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease. PubMed: 36136092DOI: 10.1021/acs.jmedchem.2c01106 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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