Identification of a novel target site for ATP-independent ERK2 inhibitors.
- Resource Type
- Article
- Authors
- Yoshida, Mayu; Nagao, Haruna; Sugiyama, Hajime; Sawa, Masaaki; Kinoshita, Takayoshi
- Source
- Biochemical & Biophysical Research Communications. Feb2022, Vol. 593, p73-78. 6p.
- Subject
- *EXTRACELLULAR signal-regulated kinases
*MOLECULAR dynamics
*BINDING site assay
*CRYSTAL structure
*BINDING sites
*DRUG target
- Language
- ISSN
- 0006-291X
Extracellular signal-regulated kinase 2 (ERK2) controls vital physiological processes involving proliferation and differentiation and is a drug target molecule for many diseases such as cancers. In silico screening focusing on an allosteric site that plays a crucial role in substrate anchoring conferred an ERK2 inhibitor (compound 1). However, a competitive binding assay indicated that compound 1 did not bind to the allosteric site. Here, the crystal structure of ERK2 in complex with compound 1 revealed a novel binding site. This finding demonstrates the feasibility of developing new types of ERK2 inhibitors. • Crystal structure of ERK2 complexed with an inhibitor were determined. • The structure conferred a novel inhibitor-binding site far from the ATP site. • The novel site was characterized by structural comparison of ERK2 with p38α and JNK1. • Molecular dynamics simulations revealed the low flexibility of the novel site in ERK2. • The finding advances the development of a new type of ERK2 inhibitors. [ABSTRACT FROM AUTHOR]