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- EMDB-29340: Cryo-EM structure of LRRK2 bound to type I inhibitor LRRK2-IN-1 -

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Basic information

Entry
Database: EMDB / ID: EMD-29340
TitleCryo-EM structure of LRRK2 bound to type I inhibitor LRRK2-IN-1
Map data
Sample
  • Complex: LRRK2-LRRK2-IN-1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one
KeywordsCryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / LRRK2-IN-1 / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / regulation of cell projection organization ...peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / regulation of cAMP/PKA signal transduction / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / regulation of synaptic vesicle transport / regulation of CAMKK-AMPK signaling cascade / regulation of lysosomal lumen pH / amphisome / co-receptor binding / mitochondrion localization / negative regulation of excitatory postsynaptic potential / regulation of retrograde transport, endosome to Golgi / regulation of dopamine receptor signaling pathway / positive regulation of microglial cell activation / positive regulation of synaptic vesicle endocytosis / negative regulation of autophagosome assembly / cytoplasmic side of mitochondrial outer membrane / neuron projection arborization / olfactory bulb development / striatum development / multivesicular body, internal vesicle / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / JUN kinase kinase kinase activity / cellular response to dopamine / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / positive regulation of programmed cell death / Wnt signalosome / negative regulation of protein processing / GTP metabolic process / regulation of canonical Wnt signaling pathway / syntaxin-1 binding / negative regulation of GTPase activity / exploration behavior / regulation of reactive oxygen species metabolic process / lysosome organization / Golgi-associated vesicle / clathrin binding / neuromuscular junction development / regulation of locomotion / PTK6 promotes HIF1A stabilization / protein kinase A binding / negative regulation of macroautophagy / regulation of synaptic vesicle exocytosis / phosphorylation / regulation of mitochondrial fission / Golgi organization / : / intracellular distribution of mitochondria / locomotory exploration behavior / regulation of synaptic vesicle endocytosis / autolysosome / endoplasmic reticulum exit site / microvillus / MAP kinase kinase kinase activity / negative regulation of Notch signaling pathway / positive regulation of protein kinase activity / Rho protein signal transduction / cellular response to manganese ion / canonical Wnt signaling pathway / presynaptic cytosol / membrane scission GTPase motor activity / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of synaptic transmission, glutamatergic / phagocytic vesicle / JNK cascade / positive regulation of autophagy / dendrite cytoplasm / negative regulation of protein binding / tubulin binding / GTPase activator activity / positive regulation of MAP kinase activity / neuron projection morphogenesis / SNARE binding / cellular response to starvation / regulation of membrane potential / positive regulation of protein ubiquitination / excitatory postsynaptic potential / regulation of autophagy / determination of adult lifespan / cellular response to reactive oxygen species / mitochondrion organization / peptidyl-threonine phosphorylation
Similarity search - Function
: / 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 / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily ...: / 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 / 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. / WD40-repeat-containing domain superfamily / Protein kinase domain / 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
Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.52 Å
AuthorsZhu H / Sun J
Funding support United States, 1 items
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
DepositionDec 29, 2022-
Header (metadata) releaseJan 17, 2024-
Map releaseJan 17, 2024-
UpdateJan 31, 2024-
Current statusJan 31, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29340.png

Downloads & links

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Map

FileDownload / File: emd_29340.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.32 Å/pix.
x 288 pix.
= 381.312 Å		1.32 Å/pix.
x 288 pix.
= 381.312 Å		1.32 Å/pix.
x 288 pix.
= 381.312 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.324 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.04
Minimum - Maximum-4.403237 - 6.8406997
Average (Standard dev.)-0.00007427426 (±0.0692468)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 381.312 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_29340_half_map_1.map
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Half map: #1

Fileemd_29340_half_map_2.map
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Sample components

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Entire : LRRK2-LRRK2-IN-1

EntireName: LRRK2-LRRK2-IN-1
Components
  • Complex: LRRK2-LRRK2-IN-1
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one

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Supramolecule #1: LRRK2-LRRK2-IN-1

SupramoleculeName: LRRK2-LRRK2-IN-1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Leucine-rich repeat serine/threonine-protein kinase 2

MacromoleculeName: Leucine-rich repeat serine/threonine-protein kinase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 136.873562 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KKAVPYNRMK LMIVGNTGSG KTTLLQQLMK TKKSDLGMQS ATVGIDVKDW PIQIRDKRKR DLVLNVWDFA GREEFYSTHP HFMTQRALY LAVYDLSKGQ AEVDAMKPWL FNIKARASSS PVILVGTHLD VSDEKQRKAC MSKITKELLN KRGFPAIRDY H FVNATEES ...String:
KKAVPYNRMK LMIVGNTGSG KTTLLQQLMK TKKSDLGMQS ATVGIDVKDW PIQIRDKRKR DLVLNVWDFA GREEFYSTHP HFMTQRALY LAVYDLSKGQ AEVDAMKPWL FNIKARASSS PVILVGTHLD VSDEKQRKAC MSKITKELLN KRGFPAIRDY H FVNATEES DALAKLRKTI INESLNFKIR DQLVVGQLIP DCYVELEKII LSERKNVPIE FPVIDRKRLL QLVRENQLQL DE NELPHAV HFLNESGVLL HFQDPALQLS DLYFVEPKWL CKIMAQILTV KVEGCPKHPK GIISRRDVEK FLSKKRKFPK NYM TQYFKL LEKFQIALPI GEEYLLVPSS LSDHRPVIEL PHCENSEIII RLYEMPYFPM GFWSRLINRL LEISPYMLSG RERA LRPNR RYWRQGIYLN WSPEAYCLVG SEVLDNHPES FLKITVPSCR KGCILLGQVV DHIDSLMEEW FPGLLEIDIC GEGET LLKK WALYSFNDGE EHQKILLDDL MKKAEEGDLL VNPDQPRLTI PISQIAPDLI LADLPRNIML NNDELEFEQA PEFLLG DGS FGSVYRAAYE GEEVAVKIFN KHTSLRLLRQ ELVVLCHLHH PSLISLLAAG IRPRMLVMEL ASKGSLDRLL QQDKASL TR TLQHRIALHV ADGLRYLHSA MIIYRDLKPH NVLLFTLYPN AAIIAKIADY GIAQYCCRMG IKTSEGTPGF RAPEVARG N VIYNQQADVY SFGLLLYDIL TTGGRIVEGL KFPNEFDELE IQGKLPDPVK EYGCAPWPMV EKLIKQCLKE NPQERPTSA QVFDILNSAE LVCLTRRILL PKNVIVECMV ATHHNSRNAS IWLGCGHTDR GQLSFLDLNT EGYTSEEVAD SRILCLALVH LPVEKESWI VSGTQSGTLL VINTEDGKKR HTLEKMTDSV TCLYCNSFSK QSKQKNFLLV GTADGKLAIF EDKTVKLKGA A PLKILNIG NVSTPLMCLS ESTNSTERNV MWGGCGTKIF SFSNDFTIQK LIETRTSQLF SYAAFSDSNI ITVVVDTALY IA KQNSPVV EVWDKKTEKL CGLIDCVHFL REVTVKENKE SKHKMSYSGR VKTLCLQKNT ALWIGTGGGH ILLLDLSTRR LIR VIYNFC NSVRVMMTAQ LGSLKNVMLV LGYNRKNTEG TQKQKEIQSC LTVWDINLPH EVQNLEKHIE VRKELAEKMR RTSV E

UniProtKB: Leucine-rich repeat serine/threonine-protein kinase 2

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Macromolecule #2: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

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

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Macromolecule #3: 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbon...

MacromoleculeName: 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one
type: ligand / ID: 3 / Number of copies: 1 / Formula: 4K4
Molecular weightTheoretical: 570.685 Da
Chemical component information

ChemComp-4K4:
2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 62.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.52 Å / Resolution method: OTHER / Software - Name: cryoSPARC / Number images used: 187407
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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