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6Y4U

Crystal structure of p38 in complex with SR65

Summary for 6Y4U
Entry DOI10.2210/pdb6y4u/pdb
DescriptorMitogen-activated protein kinase 14, 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-oxidanylidene-1-(pentan-3-ylamino)butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
Functional Keywordskinase, kinase inhibitor, mapk14, mapk, structural genomics, structural genomics consortium, sgc, transferase
Biological sourceMus musculus (House mouse)
Total number of polymer chains1
Total formula weight42216.22
Authors
Chaikuad, A.,Roehm, S.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-02-23, release date: 2020-03-04, Last modification date: 2024-01-24)
Primary citationRohm, S.,Schroder, M.,Dwyer, J.E.,Widdowson, C.S.,Chaikuad, A.,Berger, B.T.,Joerger, A.C.,Kramer, A.,Harbig, J.,Dauch, D.,Kudolo, M.,Laufer, S.,Bagley, M.C.,Knapp, S.
Selective targeting of the alpha C and DFG-out pocket in p38 MAPK.
Eur.J.Med.Chem., 208:112721-112721, 2020
Cited by
PubMed Abstract: The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.
PubMed: 33035818
DOI: 10.1016/j.ejmech.2020.112721
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.86 Å)
Structure validation

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