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- PDB-8u7h: Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915 -

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Basic information

Entry
Database: PDB / ID: 8u7h
TitleCryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915
Componentsnon-specific serine/threonine protein kinase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


regulation of multicellular organismal process / intracellular organelle lumen / regulation of intracellular signal transduction / Wnt signalosome assembly / GTP-dependent protein kinase activity / animal organ development / protein localization to endoplasmic reticulum exit site / regulation of dopamine receptor signaling pathway / regulation of vesicle-mediated transport / regulation of dendritic spine morphogenesis ...regulation of multicellular organismal process / intracellular organelle lumen / regulation of intracellular signal transduction / Wnt signalosome assembly / GTP-dependent protein kinase activity / animal organ development / protein localization to endoplasmic reticulum exit site / regulation of dopamine receptor signaling pathway / regulation of vesicle-mediated transport / regulation of dendritic spine morphogenesis / endoplasmic reticulum organization / Wnt signalosome / regulation of canonical Wnt signaling pathway / protein kinase A binding / Golgi organization / exploration behavior / endoplasmic reticulum exit site / positive regulation of protein metabolic process / regulation of proteolysis / anatomical structure morphogenesis / negative regulation of signal transduction / phagocytic vesicle / vesicle-mediated transport / positive regulation of autophagy / GTPase activator activity / regulation of membrane potential / modulation of chemical synaptic transmission / small GTPase binding / autophagy / neuron differentiation / terminal bouton / synaptic vesicle membrane / signaling receptor complex adaptor activity / protein autophosphorylation / regulation of gene expression / perikaryon / mitochondrial outer membrane / cytoskeleton / cell surface receptor signaling pathway / protein phosphorylation / lysosome / non-specific serine/threonine protein kinase / endosome / intracellular signal transduction / hydrolase activity / membrane raft / Golgi membrane / dendrite / endoplasmic reticulum membrane / GTP binding / ATP binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
: / : / : / : / LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc, COR-B domain / C-terminal of Roc (COR) domain ...: / : / : / : / LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc, COR-B domain / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Small GTPase Rab domain profile. / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Rab subfamily of small GTPases / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / WD40-repeat-containing domain superfamily / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-A0T / GUANOSINE-5'-DIPHOSPHATE / Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsZhu, H. / Sun, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R00HL143037 United States
CitationJournal: Cell Discov / Year: 2024
Title: Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.
Authors: Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun /
Abstract: LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being ...LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.
History
DepositionSep 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: non-specific serine/threonine protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,7303
Polymers136,8431
Non-polymers8872
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein non-specific serine/threonine protein kinase


Mass: 136843.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2 / Production host: Homo sapiens (human) / References: UniProt: Q17RV3
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-A0T / [4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoranyl-5-methoxy-phenyl]-morpholin-4-yl-methanone


Mass: 443.395 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21F4N5O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: LRRK2-GNE-7915 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 137 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 62.08 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
2EPUimage acquisition
4GctfCTF correction
13cryoSPARC3D reconstruction
CTF correctionType: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95644 / Symmetry type: POINT

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