4KIQ

Crystal structure of mitogen-activated protein kinase 14 (P38-H5) complex with ETHYL 6-((5-(CYCLOPROPYLCARBAMOYL)-2-METHYLPHENYL)CARBAMOYL)-1H-INDOLE-1-CARBOXYLATE

Summary for 4KIQ

• Entry DOI: 10.2210/pdb4kiq/pdb
• Related: 4KIN 4KIP
• Descriptor: Mitogen-activated protein kinase 14, ethyl 6-{[5-(cyclopropylcarbamoyl)-2-methylphenyl]carbamoyl}-1H-indole-1-carboxylate (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, kinase, transferase, p38 map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q16539
• Total number of polymer chains: 4
• Total formula weight: 170041.80

Authors

Sack, J.S.,Tokarski, J.S. (deposition date: 2013-05-02, release date: 2013-06-12, Last modification date: 2023-09-20)

Primary citation

Wrobleski, S.T.,Lin, S.,Murali Dhar, T.G.,Dyckman, A.J.,Li, T.,Pitt, S.,Zhang, R.,Fan, Y.,Doweyko, A.M.,Tokarski, J.S.,Kish, K.F.,Kiefer, S.E.,Sack, J.S.,Newitt, J.A.,Witmer, M.R.,McKinnon, M.,Barrish, J.C.,Dodd, J.H.,Schieven, G.L.,Leftheris, K.
The Identification of Novel P38-Alpha Isoform Selective Kinase Inhibitors Having an Unprecedented P38-Alpha Binding Mode
Bioorg.Med.Chem.Lett., 23:4120-4126, 2013

PubMed Abstract: A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.

PubMed: 23746475
DOI: 10.1016/j.bmcl.2013.05.047

Experimental method

X-RAY DIFFRACTION (2.5 Å)