Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125.
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.
Heo
Yong-Seok
YS
The Division of Drug Discovery, CrystalGenomics, Inc., Daeduk Biocommunity, Jeonmin-dong, Daejon, Korea.
Kim
Su-Kyoung
SK
Seo
Chang Il
CI
Kim
Young Kwan
YK
Sung
Byung-Je
BJ
Lee
Hye Shin
HS
Lee
Jae Il
JI
Park
Sam-Yong
SY
Kim
Jin Hwan
JH
Hwang
Kwang Yeon
KY
Hyun
Young-Lan
YL
Jeon
Young Ho
YH
Ro
Seonggu
S
Cho
Joong Myung
JM
Lee
Tae Gyu
TG
Yang
Chul-Hak
CH
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
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