Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability.

ABSTRACT:

Introduction

The structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood.

Objectives

To explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically exploited.

Methods

We apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active site.

Results

We demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not

SUBMITTER: Shehata MA 

PROVIDER: S-EPMC10006619 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature