title: Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125.
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.
authors.affiliation: The Division of Drug Discovery, CrystalGenomics, Inc., Daeduk Biocommunity, Jeonmin-dong, Daejon, Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Su-Kyoung
authors.initials: SK
authors.lastname: Kim
authors.forename: Chang Il
authors.initials: CI
authors.lastname: Seo
authors.forename: Young Kwan
authors.initials: YK
authors.lastname: Kim
authors.forename: Byung-Je
authors.initials: BJ
authors.lastname: Sung
authors.forename: Hye Shin
authors.initials: HS
authors.lastname: Lee
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Lee
authors.forename: Sam-Yong
authors.initials: SY
authors.lastname: Park
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Kwang Yeon
authors.initials: KY
authors.lastname: Hwang
authors.forename: Young-Lan
authors.initials: YL
authors.lastname: Hyun
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.forename: Seonggu
authors.initials: S
authors.lastname: Ro
authors.forename: Joong Myung
authors.initials: JM
authors.lastname: Cho
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Lee
authors.forename: Chul-Hak
authors.initials: CH
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D000873:Anthracenes / Q000378:metabolism*; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D015153:Blotting, Western; D002151:Calorimetry; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D007930:Leucine / Q000737:chemistry; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000873:Anthracenes; C490666:MAPK8IP1 protein, human; C432165:pyrazolanthrone; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D001120:Arginine; D011392:Proline; D048055:Mitogen-Activated Protein Kinase 8; D007930:Leucine