Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM

Abstract

LRRK2 is one of the most promising drug targets for Parkinson’s disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2–inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2–inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.

Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk

“…The deuterium uptake shows that the αC-β4 loop is very well shielded from the solvent, and the presence of MLi-2 and Rebastinib makes it even more shielded. The decrease in deuterium uptake upon MLi2 binding aligns with the recently reported MLi-2 bound LRRK2 structure [ 22 , 23 ], which shows that the binding of MLi-2 stabilizes the active conformation, making it more compact compared with the apo structure.…”

Identification of novel LRRK2 inhibitors by structure-based virtual screening and alchemical free energy calculation

“…The conformation was refined through conventional MD simulations with the corresponding scaffold inhibitors to generate representative holo conformations for use in alchemical simulations. Recently, Zhu et al elucidated the electron microscopy structure of LRRK2 bound to type I inhibitor GNE-7915 46 (PDB: , resolution: 3.80 Å). Murillo et al elucidated the electron microscopy structure of G2019S LRRK2 bound to type I inhibitor Mli-2 47 (PDB: , resolution: 2.70 Å).…”