Structural highlights
FunctionPublication Abstract from PubMedLRRK2 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. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.,Zhu H, Hixson P, Ma W, Sun J Cell Discov. 2024 Jan 23;10(1):10. doi: 10.1038/s41421-023-00639-8. PMID:38263358[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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