Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF-Pocket Allosteric Docking Site

被引：67

作者：

Busschots, Katrien ^{[1
]}

Lopez-Garcia, Laura A. ^{[1
]}

Lammi, Carmen ^{[1
]}

Stroba, Adriana ^{[2
]}

Zeuzem, Stefan ^{[1
]}

Piiper, Albrecht ^{[1
]}

Alzari, Pedro M. ^{[3
]}

Neimanis, Sonja ^{[1
]}

Arencibia, Jose M. ^{[1
]}

Engel, Matthias ^{[2
]}

Schulze, Jorg O. ^{[1
]}

Biondi, Ricardo M. ^{[1
]}

机构：

[1] Univ Frankfurt Klinikum, Dept Internal Med 1, Res Grp PhosphoSites, D-60590 Frankfurt, Germany

[2] Univ Saarland, Dept Pharmaceut & Med Chem, Res Grp PhosphoSites, D-66041 Saarbrucken, Germany

[3] Inst Pasteur, Struct Biochem Unit, F-75724 Paris, France

来源：

CHEMISTRY & BIOLOGY | 2012年 / 19卷 / 09期

关键词：

HYDROPHOBIC MOTIF PHOSPHORYLATION; IN-VIVO ROLE; CATALYTIC SUBUNIT; CRYSTAL-STRUCTURE; IRS PROTEINS; PKC-ZETA; ACTIVATION; INSULIN; DOMAIN; SPECIFICITY;

D O I：

10.1016/j.chembiol.2012.07.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The PIF-pocket of AGC protein kinases participates in the physiologic mechanism of regulation by acting as a docking site for substrates and as a switch for the transduction of the conformational changes needed for activation or inhibition. We describe the effects of compounds that bind to the PIF-pocket of PDK1. In vitro, PS210 is a potent activator of PDK1, and the crystal structure of the PDK1-ATP-PS210 complex shows that PS210 stimulates the closure of the kinase domain. However, in cells, the prodrug of PS210 (PS423) acts as a substrate-selective inhibitor of PDK1, inhibiting the phosphorylation and activation of S6K, which requires docking to the PIF-pocket, but not affecting PKB/Akt. This work describes a tool to study the dynamics of PDK1 activity and a potential approach for drug discovery.

引用

页码：1152 / 1163

页数：12

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