The p38 MAP kinase plays a crucial role in regulating the production
of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1.
Blocking this kinase may offer an effective therapy for treating
many inflammatory diseases. Here we report a new allosteric binding
site for a diaryl urea class of highly potent and selective inhibitors
against human p38 MAP kinase. The formation of this binding site
requires a large conformational change not observed previously for
any of the protein Ser/Thr kinases. This change is in the highly
conserved Asp-Phe-Gly motif within the active site of the kinase.
Solution studies demonstrate that this class of compounds has slow
binding kinetics, consistent with the requirement for conformational
change. Improving interactions in this allosteric pocket, as well
as establishing binding interactions in the ATP pocket, enhanced
the affinity of the inhibitors by 12,000-fold. One of the most potent
compounds in this series, BIRB 796, has picomolar affinity for the
kinase and low nanomolar inhibitory activity in cell culture.
%0 Journal Article
%1 Pargellis2002NSB
%A Pargellis, C.
%A Tong, L.
%A Churchill, L.
%A Cirillo, P. F.
%A Gilmore, T.
%A Graham, A. G.
%A Grob, P. M.
%A Hickey, E. R.
%A Moss, N.
%A Pav, S.
%A Regan, J.
%D 2002
%J Nat. Struct. Biol.
%K hydrophobic pocket
%P 268--272
%T Inhibition of p38 MAP kinase by utilizing a novel allosteric
binding site
%V 9
%X The p38 MAP kinase plays a crucial role in regulating the production
of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1.
Blocking this kinase may offer an effective therapy for treating
many inflammatory diseases. Here we report a new allosteric binding
site for a diaryl urea class of highly potent and selective inhibitors
against human p38 MAP kinase. The formation of this binding site
requires a large conformational change not observed previously for
any of the protein Ser/Thr kinases. This change is in the highly
conserved Asp-Phe-Gly motif within the active site of the kinase.
Solution studies demonstrate that this class of compounds has slow
binding kinetics, consistent with the requirement for conformational
change. Improving interactions in this allosteric pocket, as well
as establishing binding interactions in the ATP pocket, enhanced
the affinity of the inhibitors by 12,000-fold. One of the most potent
compounds in this series, BIRB 796, has picomolar affinity for the
kinase and low nanomolar inhibitory activity in cell culture.
@article{Pargellis2002NSB,
abstract = {The p38 MAP kinase plays a crucial role in regulating the production
of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1.
Blocking this kinase may offer an effective therapy for treating
many inflammatory diseases. Here we report a new allosteric binding
site for a diaryl urea class of highly potent and selective inhibitors
against human p38 MAP kinase. The formation of this binding site
requires a large conformational change not observed previously for
any of the protein Ser/Thr kinases. This change is in the highly
conserved Asp-Phe-Gly motif within the active site of the kinase.
Solution studies demonstrate that this class of compounds has slow
binding kinetics, consistent with the requirement for conformational
change. Improving interactions in this allosteric pocket, as well
as establishing binding interactions in the ATP pocket, enhanced
the affinity of the inhibitors by 12,000-fold. One of the most potent
compounds in this series, BIRB 796, has picomolar affinity for the
kinase and low nanomolar inhibitory activity in cell culture.},
added-at = {2009-07-08T10:06:51.000+0200},
author = {Pargellis, C. and Tong, L. and Churchill, L. and Cirillo, P. F. and Gilmore, T. and Graham, A. G. and Grob, P. M. and Hickey, E. R. and Moss, N. and Pav, S. and Regan, J.},
biburl = {https://www.bibsonomy.org/bibtex/20c18f524212f5d47ca7aec16aa422d77/coomteng},
interhash = {0485a0191a0114de4e8ad9918076e7f3},
intrahash = {0c18f524212f5d47ca7aec16aa422d77},
journal = {Nat. Struct. Biol.},
keywords = {hydrophobic pocket},
month = Apr,
pages = {268--272},
timestamp = {2009-07-08T17:40:40.000+0200},
title = {{{I}nhibition of p38 {M}{A}{P} kinase by utilizing a novel allosteric
binding site}},
volume = 9,
year = 2002
}