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Title | Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. |
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Journal, issue, pages | Cell Discov, Vol. 10, Issue 1, Page 10, Year 2024 |
Publish date | Jan 23, 2024 |
Authors | Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun / |
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 ...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. |
External links | Cell Discov / PubMed:38263358 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.4 - 3.8 Å |
Structure data | EMDB-29340, PDB-8fo7: EMDB-41982, PDB-8u7h: EMDB-41985, PDB-8u7l: EMDB-42019, PDB-8u8a: EMDB-42020, PDB-8u8b: |
Chemicals | ChemComp-GDP: ChemComp-4K4: ChemComp-A0T: ChemComp-T3X: ChemComp-0LI: ChemComp-919: |
Source |
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Keywords | HYDROLASE/HYDROLASE INHIBITOR / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / LRRK2-IN-1 / HYDROLASE-HYDROLASE INHIBITOR complex / HYDROLASE / type II inhibitor |