8smc
From Proteopedia
Cryo-EM structure of LRRK2 bound with type-I inhibitor DNL201
Structural highlights
FunctionPublication Abstract from PubMedGain-of-function mutations in LRRK2, which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the PARK16 locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.,Zhu H, Tonelli F, Turk M, Prescott A, Alessi DR, Sun J Science. 2023 Dec 22;382(6677):1404-1411. doi: 10.1126/science.adi9926. Epub 2023 , Dec 21. PMID:38127736[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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