7BE5

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

Summary for 7BE5

• Entry DOI: 10.2210/pdb7be5/pdb
• Descriptor: 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)
• Functional Keywords: mapk14, kinase inhibitor, structure-guided design, structural genomics consortium, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 42121.11

Authors

Joerger, A.C.,Schroeder, M.,Roehm, S.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-12-22, release date: 2021-03-03, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.80005236022 Å)