8U8B

Cryo-EM structure of LRRK2 bound to type II inhibitor rebastinib

Summary for 8U8B

• Entry DOI: 10.2210/pdb8u8b/pdb
• EMDB information: 42020
• Descriptor: Leucine-rich repeat serine/threonine-protein kinase 2, GUANOSINE-5'-DIPHOSPHATE, 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (3 entities in total)
• Functional Keywords: cryo-em, parkinson's disease, kinase, lrrk2, type ii inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 574848.89

Authors

Zhu, H.,Sun, J. (deposition date: 2023-09-16, release date: 2024-01-31)

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 (3.7 Å)