p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.
p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.
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DOI：
10.1016/j.jmb.2009.06.005
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发表时间：
2009-08-07
影响因子：
5.6
通讯作者：
Tainer, John A.
中科院分区：
文献类型：
--
作者：
Perry, J. Jefferson P.;Harris, Rodney M.;Moiani, Davide;Olson, Arthur J.;Tainer, John A.
The MAP kinase protein family has a critical role in cellular signaling events, with MAP kinase p38α acting in inflammatory processes and being an important drug discovery target. MAP kinase drug design efforts have focused on small molecule inhibitors of the ATP catalytic site, which exhibit dose-limiting adverse effects. Therefore, characterizing other potential sites that bind substrates, inhibitors or allosteric effectors is of great interest. Here, we present the crystal structure of p38α MAP kinase, which has a lead compound bound in both the active site and in the lipid-binding site of the C-terminal cap. This C-terminal cap is formed from an extension to the kinase fold, unique to the MAP kinase and CDK families, and GSK-3 kinase. Binding of this lead, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine, to wild-type p38α induces movement of the C-terminal cap region, creating a hydrophobic pocket centered around residue Trp197. Computational analysis of this C-Terminal domain pocket indicates notable flexibility for potentially binding different shaped compounds, including lipids, oxidized arachidonic acid species such as leukotrienes and small molecule effectors. Furthermore, our structural results defining the open p38α C-lobe pocket provide a detailed framework for the design of novel small molecules with affinities comparable to active site binders: to bind and potentially modulate the shape and activity of p38α in predetermined ways. Moreover, these results and analyses of p38α suggest strategies for designing specific binding compounds applicable to other MAP kinases, as well as the CDK kinase family and GSK-3β that also utilize the C-terminal insert in their interactions.
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影响因子：
64.5
作者：
Bourne, Y;Watson, MH;Tainer, JA
通讯作者：
Tainer, JA
影响因子：
3.5
作者：
Hung, S.-L.;Lin, Y.-J.;Chen, Y.-T.
通讯作者：
Chen, Y.-T.
影响因子：
3.5
作者：
Chiu, Shu-Jun;Chao, Jui-I;Hsu, Tzu-Sheng
通讯作者：
Hsu, Tzu-Sheng
影响因子：
50.3
作者：
Dolado, Ignacio;Swat, Aneta;Nebreda, Angel R.
通讯作者：
Nebreda, Angel R.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL