8tzb

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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/LRRK2_HUMAN 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.<ref>PMID:16352719</ref> <ref>PMID:20949042</ref> <ref>PMID:21850687</ref> <ref>PMID:22012985</ref>
[https://www.uniprot.org/uniprot/LRRK2_HUMAN 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.<ref>PMID:16352719</ref> <ref>PMID:20949042</ref> <ref>PMID:21850687</ref> <ref>PMID:22012985</ref>
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== Publication Abstract from PubMed ==
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Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-electron microscopy structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type I inhibitor MLi-2 and the broad-spectrum type II inhibitor GZD-824. Our structures revealed an active-like LRRK2 kinase in the type I inhibitor complex, and an inactive DYG-out in the type II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structures provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.
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Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.,Sanz Murillo M, Villagran Suarez A, Dederer V, Chatterjee D, Alegrio Louro J, Knapp S, Mathea S, Leschziner AE Sci Adv. 2023 Dec;9(48):eadk6191. doi: 10.1126/sciadv.adk6191. Epub 2023 Dec 1. PMID:38039358<ref>PMID:38039358</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
== References ==
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Current revision

Structure of the C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant)

PDB ID 8tzb

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