8AAU

LIM Domain Kinase 1 (LIMK1) bound to LIMKi3

8AAU の概要

• エントリーDOI: 10.2210/pdb8aau/pdb
• 分子名称: LIM domain kinase 1, 1,2-ETHANEDIOL, ~{N}-[5-[2-[2,6-bis(chloranyl)phenyl]-5-[bis(fluoranyl)methyl]pyrazol-3-yl]-1,3-thiazol-2-yl]-2-methyl-propanamide, ... (6 entities in total)
• 機能のキーワード: kinase small-molecule inhibitor cfl-1 actin cytoskeleton dynamics, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36800.62

構造登録者

Mathea, S.,Salah, E.,Hanke, T.,Knapp, S. (登録日: 2022-07-03, 公開日: 2022-08-10, 最終更新日: 2024-02-07)

主引用文献

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

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: 36136092
DOI: 10.1021/acs.jmedchem.2c01106

実験手法

X-RAY DIFFRACTION (1.74 Å)