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TitleInhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.
Journal, issue, pagesSci Adv, Vol. 9, Issue 48, Page eadk6191, Year 2023
Publish dateDec 1, 2023
AuthorsMarta Sanz Murillo / Amalia Villagran Suarez / Verena Dederer / Deep Chatterjee / Jaime Alegrio Louro / Stefan Knapp / Sebastian Mathea / Andres E Leschziner /
PubMed AbstractMutations 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 ...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.
External linksSci Adv / PubMed:38039358 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.9 Å
Structure data

EMDB-41709, PDB-8txz:
Structure of C-terminal LRRK2 bound to MLi-2
Method: EM (single particle) / Resolution: 3.05 Å

EMDB-41728, PDB-8tyq:
Structure of the C-terminal half of LRRK2 bound to GZD-824 (G2019S mutant)
Method: EM (single particle) / Resolution: 2.99 Å

EMDB-41753, PDB-8tzb:
Structure of the C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-41754, PDB-8tzc:
Structure of C-terminal LRRK2 bound to MLi-2 (G2019S mutant)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-41756, PDB-8tze:
Structure of C-terminal half of LRRK2 bound to GZD-824
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-41757, PDB-8tzf:
Structure of full length LRRK2 bound to GZD-824 (I2020T mutant)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-41758, PDB-8tzg:
Structure of C-terminal LRRK2 bound to MLi-2 (I2020T mutant)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-41759, PDB-8tzh:
Structure of full-length LRRK2 bound to MLi-2 (I2020T mutant)
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-41794: Structure of C-terminal half of LRRK2 (I2020T mutant) bound to GZD-824, Kinase-WD40
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-41795: Structure of C-terminal half of LRRK2 (I2020T mutant) bound to GZD-824, ROC-COR domain
Method: EM (single particle) / Resolution: 3.63 Å

EMDB-41797: Structure of C-terminal half of LRRK2 (G2019S mutant) bound to GZD-824, ROC-COR domain
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-41798: Structure of C-terminal half of LRRK2 bound tp GZFD-824 (G2019S mutant)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-41799: Structure of C-terminal half of LRRK2 bound to GZD-824 (G2019S mutant), Kinase-WD40
Method: EM (single particle) / Resolution: 2.99 Å

EMDB-41802: Structure of C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant)
Method: EM (single particle) / Resolution: 3.22 Å

Chemicals

ChemComp-A1N:
(2~{R},6~{S})-2,6-dimethyl-4-[6-[5-(1-methylcyclopropyl)oxy-1~{H}-indazol-3-yl]pyrimidin-4-yl]morpholine

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-HOH:
WATER

ChemComp-T3X:
4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsPROTEIN BINDING / GTPase / kinase / inhibitors / Kinase inhibitors / GTPases

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