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| Title | Structural analysis of the full-length human LRRK2. |
|---|---|
| Journal, issue, pages | Cell, Vol. 184, Issue 13, Page 3519-3527.e10, Year 2021 |
| Publish date | Jun 24, 2021 |
 Authors | Alexander Myasnikov / Hanwen Zhu / Patricia Hixson / Boer Xie / Kaiwen Yu / Aaron Pitre / Junmin Peng / Ji Sun /  |
| PubMed Abstract | 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 ...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. 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. |
 External links | Cell / PubMed:34107286 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.1 - 3.8 Å |
| Structure data | EMDB-23350, PDB-7lht: EMDB-23352, PDB-7lhw: EMDB-23359, PDB-7li3: EMDB-23360, PDB-7li4: |
| Chemicals |  ChemComp-GDP:  ChemComp-ATP: |
| Source |
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 Keywords | TRANSFERASE / HYDROLASE / Parkinson's disease / microtubule / kinase / cryo-EM / NEUROPEPTIDE |
homo sapiens (human)