4EYM

MAPK13 complex with inhibitor

4EYM の概要

• エントリーDOI: 10.2210/pdb4eym/pdb
• 関連するPDBエントリー: 4EXU 4EYJ
• 分子名称: Mitogen-activated protein kinase 13, 2-(morpholin-4-yl)-N-[4-(pyridin-4-yloxy)phenyl]pyridine-4-carboxamide (3 entities in total)
• 機能のキーワード: p38 family kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 43010.31

構造登録者

Miller, C.A.,Brett, T.J. (登録日: 2012-05-01, 公開日: 2012-12-19, 最終更新日: 2024-02-28)

主引用文献

Alevy, Y.G.,Patel, A.C.,Romero, A.G.,Patel, D.A.,Tucker, J.,Roswit, W.T.,Miller, C.A.,Heier, R.F.,Byers, D.E.,Brett, T.J.,Holtzman, M.J.
IL-13-induced airway mucus production is attenuated by MAPK13 inhibition.
J.Clin.Invest., 122:4555-4568, 2012

PubMed Abstract: Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

PubMed: 23187130
DOI: 10.1172/JCI64896

実験手法

X-RAY DIFFRACTION (2.353 Å)