2BAK

p38alpha MAP kinase bound to MPAQ

2BAK の概要

• エントリーDOI: 10.2210/pdb2bak/pdb
• 関連するPDBエントリー: 2BAJ 2BAL 2BAQ
• 分子名称: Mitogen-activated protein kinase 14, N-(3-{[7-METHOXY-6-(2-PYRROLIDIN-1-YLETHOXY)QUINAZOLIN-4-YL]AMINO}-4-METHYLPHENYL)-2-MORPHOLIN-4-YLISONICOTINAMIDE (3 entities in total)
• 機能のキーワード: p38 map kinase, serine/threonine kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42624.56

構造登録者

Gerhardt, S.,Breed, J.,Pauptit, R.A.,Read, J.,Norman, R.A.,Ward, W.H. (登録日: 2005-10-14, 公開日: 2005-12-06, 最終更新日: 2024-02-14)

主引用文献

Sullivan, J.E.,Holdgate, G.A.,Campbell, D.,Timms, D.,Gerhardt, S.,Breed, J.,Breeze, A.L.,Bermingham, A.,Pauptit, R.A.,Norman, R.A.,Embrey, K.J.,Read, J.,Vanscyoc, W.S.,Ward, W.H.
Prevention of MKK6-Dependent Activation by Binding to p38alpha MAP Kinase
Biochemistry, 44:16475-16490, 2005

PubMed Abstract: 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.

PubMed: 16342939
DOI: 10.1021/bi051714v

実験手法

X-RAY DIFFRACTION (2.2 Å)