2baj
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p38alpha bound to pyrazolourea
OverviewOverview
Inhibition of p38alpha MAP kinase is a potential approach for the, treatment of inflammatory disorders. MKK6-dependent phosphorylation on the, activation loop of p38alpha increases its catalytic activity and affinity, for ATP. An inhibitor, BIRB796, binds at a site used by the purine moiety, of ATP and extends into a "selectivity pocket", which is not used by ATP., It displaces the Asp168-Phe169-Gly170 motif at the start of the activation, loop, promoting a "DFG-out" conformation. Some other inhibitors bind only, in the purine site, with p38alpha remaining in a "DFG-in" conformation. We, now demonstrate that selectivity pocket compounds prevent MKK6-dependent, activation of p38alpha in addition to inhibiting catalysis by activated, p38alpha. Inhibitors using only the purine site do not prevent, MKK6-dependent activation. We present kinetic analyses of seven, inhibitors, whose crystal structures as complexes with p38alpha have been, determined. This work includes four new crystal structures and a novel, assay to measure K(d) for nonactivated p38alpha. Selectivity pocket, compounds associate with p38alpha over 30-fold more slowly than purine, site compounds, apparently due to low abundance of the DFG-out, conformation. At concentrations that inhibit cellular production of an, inflammatory cytokine, TNFalpha, selectivity pocket compounds decrease, levels of phosphorylated p38alpha and beta. Stabilization of a DFG-out, conformation appears to interfere with recognition of p38alpha as a, substrate by MKK6. ATP competes less effectively for prevention of, activation than for inhibition of catalysis. By binding to a different, conformation of the enzyme, compounds that prevent activation offer an, alternative approach to modulation of p38alpha.
About this StructureAbout this Structure
2BAJ is a Single protein structure of sequence from Homo sapiens with 1PP as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
ReferenceReference
Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase., Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, Breeze AL, Bermingham A, Pauptit RA, Norman RA, Embrey KJ, Read J, VanScyoc WS, Ward WH, Biochemistry. 2005 Dec 20;44(50):16475-90. PMID:16342939
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