| Structural highlights
Disease
LRRK2_HUMAN Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:607060. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]
Function
LRRK2_HUMAN May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes.[35] [36] [37] [38]
Publication Abstract from PubMed
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.
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[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Angeles DC, Gan BH, Onstead L, Zhao Y, Lim KL, Dachsel J, Melrose H, Farrer M, Wszolek ZK, Dickson DW, Tan EK. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Hum Mutat. 2011 Dec;32(12):1390-7. doi: 10.1002/humu.21582. Epub 2011 Sep 12. PMID:21850687 doi:10.1002/humu.21582
- ↑ Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012 Feb 1;21(3):511-25. doi: 10.1093/hmg/ddr481. Epub 2011 Oct, 19. PMID:22012985 doi:10.1093/hmg/ddr481
- ↑ Zhu H, Hixson P, Ma W, Sun J. Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. Cell Discov. 2024 Jan 23;10(1):10. PMID:38263358 doi:10.1038/s41421-023-00639-8
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