6Y4U

Crystal structure of p38 in complex with SR65

Summary for 6Y4U

• Entry DOI: 10.2210/pdb6y4u/pdb
• Descriptor: Mitogen-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 Keywords: kinase, kinase inhibitor, mapk14, mapk, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Mus musculus (House mouse)
• Total number of polymer chains: 1
• Total formula weight: 42216.22

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 citation

Rohm, 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

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

Experimental method

X-RAY DIFFRACTION (1.86 Å)