8SMC
Cryo-EM structure of LRRK2 bound with type-I inhibitor DNL201
Summary for 8SMC
| Entry DOI | 10.2210/pdb8smc/pdb |
| EMDB information | 40588 |
| Descriptor | non-specific serine/threonine protein kinase, GUANOSINE-5'-DIPHOSPHATE, 2-methyl-2-(3-methyl-4-{[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-pyrazol-1-yl)propanenitrile (3 entities in total) |
| Functional Keywords | parkinson's disease, kinase, activation, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 137625.99 |
| Authors | |
| Primary citation | Zhu, H.,Tonelli, F.,Turk, M.,Prescott, A.,Alessi, D.R.,Sun, J. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Science, 382:1404-1411, 2023 Cited by PubMed Abstract: Gain-of-function mutations in , 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 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. PubMed: 38127736DOI: 10.1126/science.adi9926 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (4.02 Å) |
Structure validation
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