8TZH

Structure of full-length LRRK2 bound to MLi-2 (I2020T mutant)

Summary for 8TZH

• Entry DOI: 10.2210/pdb8tzh/pdb
• Related: 8TXZ 8TZC 8TZG
• EMDB information: 41759
• Descriptor: E11 DARPin, Leucine-rich repeat serine/threonine-protein kinase 2, (2~{R},6~{S})-2,6-dimethyl-4-[6-[5-(1-methylcyclopropyl)oxy-1~{H}-indazol-3-yl]pyrimidin-4-yl]morpholine, ... (4 entities in total)
• Functional Keywords: gtpase, kinase, inhibitors, protein binding
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 307052.35

Authors

Sanz-Murillo, M.,Villagran-Suarez, A.,Alegrio Louro, J.,Leschziner, A. (deposition date: 2023-08-26, release date: 2023-12-06, Last modification date: 2023-12-13)

Primary citation

Sanz Murillo, M.,Villagran Suarez, A.,Dederer, V.,Chatterjee, D.,Alegrio Louro, J.,Knapp, S.,Mathea, S.,Leschziner, A.E.
Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.
Sci Adv, 9:eadk6191-eadk6191, 2023

PubMed Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-electron microscopy structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type I inhibitor MLi-2 and the broad-spectrum type II inhibitor GZD-824. Our structures revealed an active-like LRRK2 kinase in the type I inhibitor complex, and an inactive DYG-out in the type II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structures provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.

PubMed: 38039358
DOI: 10.1126/sciadv.adk6191

Experimental method

ELECTRON MICROSCOPY (3.9 Å)