cb2c00868_si_004.avi (2.89 MB)
Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors
mediaposted on 2023-04-12, 21:43 authored by Jui-Hung Weng, Wen Ma, Jian Wu, Pallavi Kaila Sharma, Steve Silletti, J. Andrew McCammon, Susan Taylor
Mutations in the human leucine rich repeat protein kinase-2 (LRRK2) create risk factors for Parkinson’s disease, and pathological functions of LRRK2 are often correlated with aberrant kinase activity. Past research has focused on developing selective LRRK2 kinase inhibitors. In this study, we combined enhanced sampling simulations with HDX-MS to characterize the inhibitor-induced dynamic changes and the allosteric communications within the C-terminal domains of LRRK2, LRRK2RCKW. We find that the binding of MLi-2 (a type I kinase inhibitor) stabilizes a closed kinase conformation and reduces the global dynamics of LRRK2RCKW, leading to a more compact LRRK2RCKW structure. In contrast, the binding of Rebastinib (a type II kinase inhibitor) stabilizes an open kinase conformation, which promotes a more extended LRRK2RCKW structure. By probing the distinct effects of the type I and type II inhibitors, key interdomain interactions are found to regulate the communication between the kinase domain and the GTPase domain. The intermediate states revealed in our simulations facilitate the efforts toward in silico design of allosteric modulators that control LRRK2 conformations and potentially mediate the oligomeric states of LRRK2 and its interactions with other proteins.
induced dynamic changescreate risk factorsopen kinase conformationclosed kinase conformationaberrant kinase activityallosteric communications withinintermediate states revealedtype ii inhibitorskey interdomain interactionscontrol lrrk2 conformationsrckw supkinase domainsilico allosteric modulatorsoligomeric statesconformational stateskinase inhibitorterminal domainssimulations facilitatepotentially mediatepathological functionspast researchparkinson ’often correlatedlrrk2 dynamicsgtpase domainglobal dynamicsextended lrrk2efforts towarddistinct effectscompact lrrk2capturing differences