7LHT

Structure of the LRRK2 dimer

Summary for 7LHT

• Entry DOI: 10.2210/pdb7lht/pdb
• EMDB information: 23350
• Descriptor: Leucine-rich repeat serine/threonine-protein kinase 2, GUANOSINE-5'-DIPHOSPHATE, ADENOSINE-5'-TRIPHOSPHATE (3 entities in total)
• Functional Keywords: parkinson's disease, microtubule, kinase, cryo-em, neuropeptide, transferase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 574756.08

Authors

Myasnikov, A.,Zhu, H.,Hixson, P.,Xie, B.,Yu, K.,Pitre, A.,Peng, J.,Sun, J. (deposition date: 2021-01-26, release date: 2021-06-16, Last modification date: 2024-03-06)

Primary citation

Myasnikov, A.,Zhu, H.,Hixson, P.,Xie, B.,Yu, K.,Pitre, A.,Peng, J.,Sun, J.
Structural analysis of the full-length human LRRK2.
Cell, 184:3519-, 2021

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 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.

PubMed: 34107286
DOI: 10.1016/j.cell.2021.05.004

Experimental method

ELECTRON MICROSCOPY (3.5 Å)