Dataset Information


A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.

ABSTRACT: Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix ?C. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.

SUBMITTER: Chaikuad A 

PROVIDER: S-EPMC4687050 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC4083111 | BioStudies
2005-01-01 | S-EPMC1366515 | BioStudies
1997-01-01 | S-EPMC1218137 | BioStudies
1000-01-01 | S-EPMC4155088 | BioStudies
2017-01-01 | S-EPMC5666907 | BioStudies
2020-01-01 | S-EPMC7294809 | BioStudies
2020-01-01 | S-EPMC7411023 | BioStudies
2018-01-01 | S-EPMC5757254 | BioStudies
2012-01-01 | S-EPMC4016787 | BioStudies
2017-01-01 | S-EPMC5555573 | BioStudies