Inhibition of Parkinsons Disease-related LRRK2 by type-I and type-II kinase inhibitors: activity and structures

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are a common cause of familial Parkinsons Disease (PD), and a risk factor for the sporadic form. Increased kinase activity has been shown in both familial and sporadic PD patients, making LRRK2 kinase inhibitors a major focus of drug development efforts in PD. Although significant progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-EM structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type-I inhibitor MLi-2 and the broad-spectrum type-II inhibitor GZD-824. Our structures revealed LRRK2s kinase in the active-like state, stabilized by type-I inhibitor interactions, and an inactive DYG-out type-II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structural models provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.