7BE5

Crystal structure of MAP kinase p38 alpha in complex with inhibitor SR276

7BE5 の概要

• エントリーDOI: 10.2210/pdb7be5/pdb
• 分子名称: Mitogen-activated protein kinase 14, 1,2-ETHANEDIOL, 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-[[(3~{R})-1-methylsulfonylpiperidin-3-yl]amino]-1-oxidanylidene-butan-2-yl]carbamoyl]phenyl]methyl]-1-methyl-pyrazole-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: mapk14, kinase inhibitor, structure-guided design, structural genomics consortium, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42121.11

構造登録者

Joerger, A.C.,Schroeder, M.,Roehm, S.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-12-22, 公開日: 2021-03-03, 最終更新日: 2024-01-31)

主引用文献

Rohm, S.,Berger, B.T.,Schroder, M.,Chatterjee, D.,Mathea, S.,Joerger, A.C.,Pinkas, D.M.,Bufton, J.C.,Tjaden, A.,Kovooru, L.,Kudolo, M.,Pohl, C.,Bullock, A.N.,Muller, S.,Laufer, S.,Knapp, S.
Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe.
J.Med.Chem., 64:13451-13474, 2021

PubMed Abstract: Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal and pulmonary fibrosis, atherosclerosis, and various forms of cancer. Potent and selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases such as the tyrosine protein kinase receptor TIE or tropomyosin receptor kinases, which are related to angiogenesis and neuronal toxicity. In this study, we optimized our recently published p38 mitogen-activated protein kinase inhibitor toward a potent and cell-active dual DDR/p38 chemical probe and developed a structurally related negative control. The structure-guided design approach used provided insights into the P-loop folding process of p38 and how targeting of non-conserved amino acids modulates inhibitor selectivity. The developed and comprehensively characterized DDR/p38 probe, (SR-302), is a valuable tool for studying the role of DDR kinase in normal physiology and in disease development.

PubMed: 34506142
DOI: 10.1021/acs.jmedchem.1c00868

実験手法

X-RAY DIFFRACTION (1.80005236022 Å)