3NNU

Crystal structure of P38 alpha in complex with DP1376

Summary for 3NNU

• Entry DOI: 10.2210/pdb3nnu/pdb
• Related: 3NNV 3NNW 3NNX
• Descriptor: Mitogen-activated protein kinase 14, 2-{3-[(5E)-5-{[(2,3-dichlorophenyl)carbamoyl]imino}-3-thiophen-2-yl-2,5-dihydro-1H-pyrazol-1-yl]phenyl}acetamide (3 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 41095.82

Authors

Abendroth, J. (deposition date: 2010-06-24, release date: 2010-09-15, Last modification date: 2023-12-27)

Primary citation

Ahn, Y.M.,Clare, M.,Ensinger, C.L.,Hood, M.M.,Lord, J.W.,Lu, W.P.,Miller, D.F.,Patt, W.C.,Smith, B.D.,Vogeti, L.,Kaufman, M.D.,Petillo, P.A.,Wise, S.C.,Abendroth, J.,Chun, L.,Clark, R.,Feese, M.,Kim, H.,Stewart, L.,Flynn, D.L.
Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region
Bioorg.Med.Chem.Lett., 20:5793-5798, 2010

PubMed Abstract: Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.

PubMed: 20800479
DOI: 10.1016/j.bmcl.2010.07.134

Experimental method

X-RAY DIFFRACTION (2.4 Å)