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
收藏
页码:1152 / 1163
页数:12
相关论文
共 40 条
[1]   Chronically Increased S6K1 Is Associated with Impaired IRS1 Signaling in Skeletal Muscle of GDM Women with Impaired Glucose Tolerance Postpartum [J].
Barbour, Linda A. ;
McCurdy, Carrie E. ;
Hernandez, Teri L. ;
Friedman, Jacob E. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2011, 96 (05) :1431-1441
[2]   Snapping of the carboxyl terminal tail of the catalytic subunit of PKA onto its core: Characterization of the sites by mutagenesis [J].
Batkin, M ;
Schvartz, I ;
Shaltiel, S .
BIOCHEMISTRY, 2000, 39 (18) :5366-5373
[3]   Evaluation of approaches to generation of tissue-specific knock-in mice [J].
Bayascas, Jose R. ;
Sakamoto, Kei ;
Armit, Laura ;
Arthur, J. Simon C. ;
Alessi, Dario R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (39) :28772-28781
[4]   Phosphoinositide-dependent protein kinase 1, a sensor of protein conformation [J].
Biondi, RM .
TRENDS IN BIOCHEMICAL SCIENCES, 2004, 29 (03) :136-142
[5]   The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB [J].
Biondi, RM ;
Kieloch, A ;
Currie, RA ;
Deak, M ;
Alessi, DR .
EMBO JOURNAL, 2001, 20 (16) :4380-4390
[6]   High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site [J].
Biondi, RM ;
Komander, D ;
Thomas, CC ;
Lizcano, JM ;
Deak, M ;
Alessi, DR ;
van Aalten, DMF .
EMBO JOURNAL, 2002, 21 (16) :4219-4228
[7]   Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions [J].
Biondi, RM ;
Nebreda, AR .
BIOCHEMICAL JOURNAL, 2003, 372 :1-13
[8]   Discovery of PDK1 Kinase Inhibitors with a Novel Mechanism of Action by Ultrahigh Throughput Screening [J].
Bobkova, Ekaterina V. ;
Weber, Michael J. ;
Xu, Zangwei ;
Zhang, Yan-Ling ;
Jung, Joon ;
Blume-Jensen, Peter ;
Northrup, Alan ;
Kunapuli, Priya ;
Andersen, Jannik N. ;
Kariv, Ilona .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (24) :18838-18846
[9]   Phosphorylation of IRS proteins, insulin action, and insulin resistance [J].
Boura-Halfon, Sigalit ;
Zick, Yehiel .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2009, 296 (04) :E581-E591
[10]   Protein kinases - the major drug targets of the twenty-first century? [J].
Cohen, P .
NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (04) :309-315