8FO7

Cryo-EM structure of LRRK2 bound to type I inhibitor LRRK2-IN-1

Summary for 8FO7

• Entry DOI: 10.2210/pdb8fo7/pdb
• EMDB information: 29340
• Descriptor: Leucine-rich repeat serine/threonine-protein kinase 2, GUANOSINE-5'-DIPHOSPHATE, 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one (3 entities in total)
• Functional Keywords: cryo-em, parkinson's disease, kinase, lrrk2, type i inhibitor, lrrk2-in-1, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 137887.45

Authors

Zhu, H.,Sun, J. (deposition date: 2022-12-29, release date: 2024-01-17, Last modification date: 2025-05-14)

Primary citation

Zhu, H.,Hixson, P.,Ma, W.,Sun, J.
Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.
Cell Discov, 10:10-10, 2024

PubMed 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.

PubMed: 38263358
DOI: 10.1038/s41421-023-00639-8

Experimental method

ELECTRON MICROSCOPY (3.52 Å)