Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125

被引:241
作者
Heo, JS
Kim, SK
Seo, CI
Kim, YK
Sung, BJ
Lee, HS
Lee, JI
Park, SY
Kim, JH
Hwang, KY
Hyun, YL
Jeon, YH
Ro, S
Cho, JM
Lee, TG
Yang, CH
机构
[1] CrystalGenom Inc, Div Drug Discovery, Taejon 305390, South Korea
[2] Seoul Natl Univ, Sch Chem & Mol Engn, Mol Enzymol Lab, Seoul, South Korea
[3] Yokohama City Univ, Prot Design Lab, Yokohama, Kanagawa 232, Japan
关键词
docking site; JIP1; JNK; scaffolding protein; SP600125;
D O I
10.1038/sj.emboj.7600212
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 c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by cytoplasmic retention of JNK and thereby inhibits gene expression mediated by JNK, which occurs in the nucleus. Here, we report the crystal structure of human JNK1 complexed with pepJIP1, the peptide fragment of JIP1, revealing its selectivity for JNK1 over other MAPKs and the allosteric inhibition mechanism. The van der Waals contacts by the three residues (Pro157, Leu160, and Leu162) of pepJIP1 and the hydrogen bonding between Glu329 of JNK1 and Arg156 of pepJIP1 are critical for the selective binding. Binding of the peptide also induces a hinge motion between the Nand C-terminal domains of JNK1 and distorts the ATP-binding cleft, reducing the affinity of the kinase for ATP. In addition, we also determined the ternary complex structure of pepJIP1-bound JNK1 complexed with SP600125, an ATP-competitive inhibitor of JNK, providing the basis for the JNK specificity of the compound.
引用
收藏
页码:2185 / 2195
页数:11
相关论文
共 43 条
[1]   The specificities of protein kinase inhibitors: an update [J].
Bain, J ;
McLauchlan, H ;
Elliott, M ;
Cohen, P .
BIOCHEMICAL JOURNAL, 2003, 371 :199-204
[2]   A conserved docking site in MEKs mediates high-affinity binding to MAP kinases and cooperates with a scaffold protein to enhance signal transmission [J].
Bardwell, AJ ;
Flatauer, LJ ;
Matsukuma, K ;
Thorner, J ;
Bardwell, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (13) :10374-10386
[3]   Identification of the critical features of a small peptide inhibitor of JNK activity [J].
Barr, RK ;
Kendrick, TS ;
Bogoyevitch, MA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (13) :10987-10997
[4]   SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase [J].
Bennett, BL ;
Sasaki, DT ;
Murray, BW ;
O'Leary, EC ;
Sakata, ST ;
Xu, WM ;
Leisten, JC ;
Motiwala, A ;
Pierce, S ;
Satoh, Y ;
Bhagwat, SS ;
Manning, AM ;
Anderson, DW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (24) :13681-13686
[5]   Cell-permeable peptide inhibitors of JNK novel blockers of β-cell death [J].
Bonny, C ;
Oberson, A ;
Negri, S ;
Sauser, C ;
Schorderet, DF .
DIABETES, 2001, 50 (01) :77-82
[6]   Targeting the JNK Pathway for Therapeutic Benefit in CNS Disease [J].
Bozyczko-Coyne, Donna ;
Saporito, Michael S. ;
Hudkins, Robert L. .
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2002, 1 (01) :31-49
[7]   Crystal structure of the complex of the cyclin D dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d [J].
Brotherton, DH ;
Dhanaraj, V ;
Wick, S ;
Brizuela, L ;
Domaille, PJ ;
Volyanik, E ;
Xu, X ;
Parisini, E ;
Smith, BO ;
Archer, SJ ;
Serrano, M ;
Brenner, SL ;
Blundell, TL ;
Laue, ED .
NATURE, 1998, 395 (6699) :244-250
[8]  
Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254
[9]   Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b [J].
Chang, CI ;
Xu, BE ;
Akella, R ;
Cobb, MH ;
Goldsmith, EJ .
MOLECULAR CELL, 2002, 9 (06) :1241-1249
[10]   Signal transduction by the JNK group of MAP kinases [J].
Davis, RJ .
CELL, 2000, 103 (02) :239-252