Summary for 6ZWP
| Entry DOI | 10.2210/pdb6zwp/pdb |
| Descriptor | Mitogen-activated protein kinase 14, 5-azanyl-~{N}-[[4-[[(2~{S})-4-cyclohexyl-1-[(4-fluorophenyl)amino]-1-oxidanylidene-butan-2-yl]carbamoyl]phenyl]methyl]-1-phenyl-pyrazole-4-carboxamide (3 entities in total) |
| Functional Keywords | kinase, inhibitor, p38a, structural genomics, structural genomics consortium, sgc, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41991.91 |
| Authors | Schroeder, M.,Roehm, S.,Knapp, S.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.M.,Structural Genomics Consortium (SGC) (deposition date: 2020-07-28, release date: 2020-08-12, Last modification date: 2024-01-31) |
| 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 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: 33035818DOI: 10.1016/j.ejmech.2020.112721 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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