Article
- The EMBO Journal (2004) 23, 2185 - 2195
- doi:10.1038/sj.emboj.7600212
Published online: 13 May 2004
Subject Categories:
Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125
Yong-Seok Heo1,2, Su-Kyoung Kim1, Chang Il Seo1, Young Kwan Kim1, Byung-Je Sung1, Hye Shin Lee1, Jae Il Lee1, Sam-Yong Park3, Jin Hwan Kim1, Kwang Yeon Hwang1, Young-Lan Hyun1, Young Ho Jeon1, Seonggu Ro1, Joong Myung Cho1, Tae Gyu Lee1 and Chul-Hak Yang2
- The Division of Drug Discovery, CrystalGenomics, Inc., Daeduk Biocommunity, Jeonmin-dong, Yuseong-gu, Daejon, Korea
- Molecular Enzymology Laboratory, School of Chemistry and Molecular Engineering, Seoul National University, Seoul, Korea
- Protein Design Laboratory, Yokohama City University, Suechiro-cho, Tsurumi, Yokohama, Japan
Correspondence to:
Tae Gyu Lee, CrystalGenomics, Inc., Daeduk Biocommunity, Jeonmin-dong, Yuseong-gu, Daejeon 305-390, Korea. Tel.: +82 42 866 9320; Fax: +82 42 866 9301; E-mail: tglee@crystalgenomics.com
Chul-Hak Yang, Molecular Enzymology Laboratory, School of Chemistry and Molecular Engineering, Seoul National University, NS60, Seoul 151-742, Korea. Tel.: +82 2 878 8545; Fax: +82 2 889 1568; E-mail: chulyang@plaza.snu.ac.kr
Received 28 August 2003; Accepted 22 March 2004
Abstract
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 N- and 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.
Keywords:
- docking site,
- JIP1,
- JNK,
- scaffolding protein,
- SP600125
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