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==Structure of the LRRK2 monomer==
==Structure of the LRRK2 monomer==
<StructureSection load='7lhw' size='340' side='right'caption='[[7lhw]]' scene=''>
<StructureSection load='7lhw' size='340' side='right'caption='[[7lhw]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LHW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LHW FirstGlance]. <br>
<table><tr><td colspan='2'>[[7lhw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LHW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LHW FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lhw OCA], [https://pdbe.org/7lhw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lhw RCSB], [https://www.ebi.ac.uk/pdbsum/7lhw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lhw ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LRRK2, PARK8 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lhw OCA], [https://pdbe.org/7lhw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lhw RCSB], [https://www.ebi.ac.uk/pdbsum/7lhw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lhw ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/LRRK2_HUMAN LRRK2_HUMAN]] Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:[https://omim.org/entry/607060 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.<ref>PMID:21850687</ref> <ref>PMID:16321986</ref> <ref>PMID:16269541</ref> <ref>PMID:15541309</ref> <ref>PMID:15541308</ref> <ref>PMID:16081470</ref> <ref>PMID:16087219</ref> <ref>PMID:15726496</ref> <ref>PMID:15732108</ref> <ref>PMID:15852371</ref> <ref>PMID:16240353</ref> <ref>PMID:15880653</ref> <ref>PMID:15929036</ref> <ref>PMID:16251215</ref> <ref>PMID:16272164</ref> <ref>PMID:16333314</ref> <ref>PMID:16272257</ref> <ref>PMID:15680455</ref> <ref>PMID:15680456</ref> <ref>PMID:15680457</ref> <ref>PMID:15811454</ref> <ref>PMID:16250030</ref> <ref>PMID:16172858</ref> <ref>PMID:16157901</ref> <ref>PMID:16247070</ref> <ref>PMID:16157908</ref> <ref>PMID:16157909</ref> <ref>PMID:15925109</ref> <ref>PMID:16298482</ref> <ref>PMID:16102999</ref> <ref>PMID:16533964</ref> <ref>PMID:17019612</ref> <ref>PMID:18213618</ref> <ref>PMID:21641266</ref> 
== 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at membranous organelles and forms microtubule-based pathogenic filaments, yet the molecular basis underlying these biological roles of LRRK2 remains largely enigmatic. Here, we determined high-resolution structures of full-length human LRRK2, revealing its architecture and key interdomain scaffolding elements for rationalizing disease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state, a conformation also adopted by the most common PD-associated mutation, LRRK2(G2019S). This conformation serves as a framework for structure-guided design of conformational specific inhibitors. We further determined the structure of COR-mediated LRRK2 dimers and found that single-point mutations at the dimer interface abolished pathogenic filamentation in cells. Overall, our study provides mechanistic insights into physiological and pathological roles of LRRK2 and establishes a structural template for future therapeutic intervention in PD.
Structural analysis of the full-length human LRRK2.,Myasnikov A, Zhu H, Hixson P, Xie B, Yu K, Pitre A, Peng J, Sun J Cell. 2021 Jun 3. pii: S0092-8674(21)00601-2. doi: 10.1016/j.cell.2021.05.004. PMID:34107286<ref>PMID:34107286</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lhw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Hixson P]]
[[Category: Hixson, P]]
[[Category: Myasnikov A]]
[[Category: Myasnikov, A]]
[[Category: Peng J]]
[[Category: Peng, J]]
[[Category: Pitre A]]
[[Category: Pitre, A]]
[[Category: Sun J]]
[[Category: Sun, J]]
[[Category: Xie B]]
[[Category: Xie, B]]
[[Category: Yu K]]
[[Category: Yu, K]]
[[Category: Zhu H]]
[[Category: Zhu, H]]
[[Category: Cryo-em]]
[[Category: Hydrolase]]
[[Category: Kinase]]
[[Category: Microtubule]]
[[Category: Neuropeptide]]
[[Category: Parkinson's disease]]
[[Category: Transferase]]
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