6C6M

IgCam3 of human MLCK1

6C6M の概要

• エントリーDOI: 10.2210/pdb6c6m/pdb
• 分子名称: Myosin light chain kinase, smooth muscle (2 entities in total)
• 機能のキーワード: igcam mlck1 ibd, cell adhesion
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 34898.90

構造登録者

Zuccola, H.J.,Turner, J. (登録日: 2018-01-19, 公開日: 2019-01-23, 最終更新日: 2024-03-06)

主引用文献

Graham, W.V.,He, W.,Marchiando, A.M.,Zha, J.,Singh, G.,Li, H.S.,Biswas, A.,Ong, M.L.D.M.,Jiang, Z.H.,Choi, W.,Zuccola, H.,Wang, Y.,Griffith, J.,Wu, J.,Rosenberg, H.J.,Wang, Y.,Snapper, S.B.,Ostrov, D.,Meredith, S.C.,Miller, L.W.,Turner, J.R.
Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis.
Nat. Med., 25:690-700, 2019

PubMed Abstract: Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.

PubMed: 30936544
DOI: 10.1038/s41591-019-0393-7

実験手法

X-RAY DIFFRACTION (2.5 Å)