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- EMDB-42020: Cryo-EM structure of LRRK2 bound to type II inhibitor rebastinib -

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Entry
Database: EMDB / ID: EMD-42020
TitleCryo-EM structure of LRRK2 bound to type II inhibitor rebastinib
Map data
Sample
  • Complex: LRRK2-rebastinib
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
KeywordsCryo-EM / Parkinson's disease / Kinase / LRRK2 / type II inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


caveola neck / : / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / Wnt signalosome assembly / regulation of kidney size / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / GTP-dependent protein kinase activity / regulation of SNARE complex assembly ...caveola neck / : / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / Wnt signalosome assembly / regulation of kidney size / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / GTP-dependent protein kinase activity / regulation of SNARE complex assembly / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / protein localization to endoplasmic reticulum exit site / peroxidase inhibitor activity / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / : / positive regulation of dopamine receptor signaling pathway / amphisome / regulation of synaptic vesicle transport / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / co-receptor binding / negative regulation of GTPase activity / regulation of dopamine receptor signaling pathway / positive regulation of microglial cell activation / regulation of neuron maturation / regulation of retrograde transport, endosome to Golgi / positive regulation of synaptic vesicle endocytosis / negative regulation of excitatory postsynaptic potential / cytoplasmic side of mitochondrial outer membrane / negative regulation of autophagosome assembly / olfactory bulb development / JUN kinase kinase kinase activity / neuron projection arborization / striatum development / multivesicular body, internal vesicle / regulation of dendritic spine morphogenesis / mitochondrion localization / protein localization to mitochondrion / cellular response to dopamine / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / Wnt signalosome / negative regulation of protein processing / positive regulation of programmed cell death / GTP metabolic process / regulation of canonical Wnt signaling pathway / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / lysosome organization / Golgi-associated vesicle / clathrin binding / PTK6 promotes HIF1A stabilization / negative regulation of macroautophagy / neuromuscular junction development / regulation of cAMP/PKA signal transduction / regulation of mitochondrial fission / protein kinase A binding / regulation of locomotion / regulation of synaptic vesicle exocytosis / Golgi organization / intracellular distribution of mitochondria / microvillus / exploration behavior / endoplasmic reticulum exit site / autolysosome / locomotory exploration behavior / negative regulation of Notch signaling pathway / regulation of synaptic vesicle endocytosis / MAP kinase kinase kinase activity / canonical Wnt signaling pathway / regulation of synaptic transmission, glutamatergic / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / Rho protein signal transduction / presynaptic cytosol / neuron projection morphogenesis / phagocytic vesicle / cellular response to manganese ion / JNK cascade / positive regulation of autophagy / dendrite cytoplasm / tubulin binding / GTPase activator activity / cellular response to starvation / positive regulation of protein ubiquitination / SNARE binding / determination of adult lifespan / regulation of membrane potential / cellular response to reactive oxygen species / excitatory postsynaptic potential / mitochondrion organization / trans-Golgi network / calcium-mediated signaling / regulation of protein stability / autophagy / small GTPase binding / mitochondrial membrane / endocytosis
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 / C-terminal of Roc, COR-A 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 / 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
Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 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
DepositionSep 16, 2023-
Header (metadata) releaseJan 31, 2024-
Map releaseJan 31, 2024-
UpdateJan 31, 2024-
Current statusJan 31, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42020.png

Downloads & links

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Map

FileDownload / File: emd_42020.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 384 pix.
= 498.048 Å		1.3 Å/pix.
x 384 pix.
= 498.048 Å		1.3 Å/pix.
x 384 pix.
= 498.048 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.297 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-2.2225559 - 3.8617008
Average (Standard dev.)0.00158128 (±0.06054718)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 498.04803 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #2

Fileemd_42020_additional_1.map
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Additional map: #1

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Half map: #2

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Half map: #1

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Sample components

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Entire : LRRK2-rebastinib

EntireName: LRRK2-rebastinib
Components
  • Complex: LRRK2-rebastinib
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide

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Supramolecule #1: LRRK2-rebastinib

SupramoleculeName: LRRK2-rebastinib / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 286 kDa/nm

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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: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 286.427656 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH ...String:
MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSEH ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH SFPANDEVQK LGCKALHVLF ERVSEEQLTE FVENKDYMIL LSALTNFKDE EEIVLHVLHC LHSLAIPCNN VE VLMSGNV RCYNIVVEAM KAFPMSERIQ EVSCCLLHRL TLGNFFNILV LNEVHEFVVK AVQQYPENAA LQISALSCLA LLT ETIFLN QDLEEKNENQ ENDDEGEEDK LFWLEACYKA LTWHRKNKHV QEAACWALNN LLMYQNSLHE KIGDEDGHFP AHRE VMLSM LMHSSSKEVF QASANALSTL LEQNVNFRKI LLSKGIHLNV LELMQKHIHS PEVAESGCKM LNHLFEGSNT SLDIM AAVV PKILTVMKRH ETSLPVQLEA LRAILHFIVP GMPEESREDT EFHHKLNMVK KQCFKNDIHK LVLAALNRFI GNPGIQ KCG LKVISSIVHF PDALEMLSLE GAMDSVLHTL QMYPDDQEIQ CLGLSLIGYL ITKKNVFIGT GHLLAKILVS SLYRFKD VA EIQTKGFQTI LAILKLSASF SKLLVHHSFD LVIFHQMSSN IMEQKDQQFL NLCCKCFAKV AMDDYLKNVM LERACDQN N SIMVECLLLL GADANQAKEG SSLICQVCEK ESSPKLVELL LNSGSREQDV RKALTISIGK GDSQIISLLL RRLALDVAN NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQ SDDLDSEGSE GSFLVKKKSN SISVGEFYRD AVLQRCSPNL QRHSNSLGPI FDHEDLLKRK RKILSSDDSL R SSKLQSHM RHSDSISSLA SEREYITSLD LSANELRDID ALSQKCCISV HLEHLEKLEL HQNALTSFPQ QLCETLKSLT HL DLHSNKF TSFPSYLLKM SCIANLDVSR NDIGPSVVLD PTVKCPTLKQ FNLSYNQLSF VPENLTDVVE KLEQLILEGN KIS GICSPL RLKELKILNL SKNHISSLSE NFLEACPKVE SFSARMNFLA AMPFLPPSMT ILKLSQNKFS CIPEAILNLP HLRS LDMSS NDIQYLPGPA HWKSLNLREL LFSHNQISIL DLSEKAYLWS RVEKLHLSHN KLKEIPPEIG CLENLTSLDV SYNLE LRSF PNEMGKLSKI WDLPLDELHL NFDFKHIGCK AKDIIRFLQQ RLKKAVPYNR MKLMIVGNTG SGKTTLLQQL MKTKKS DLG MQSATVGIDV KDWPIQIRDK RKRDLVLNVW DFAGREEFYS THPHFMTQRA LYLAVYDLSK GQAEVDAMKP WLFNIKA RA SSSPVILVGT HLDVSDEKQR KACMSKITKE LLNKRGFPAI RDYHFVNATE ESDALAKLRK TIINESLNFK IRDQLVVG Q LIPDCYVELE KIILSERKNV PIEFPVIDRK RLLQLVRENQ LQLDENELPH AVHFLNESGV LLHFQDPALQ LSDLYFVEP KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMTQYF KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSE IIIRLYEMPY FPMGFWSRLI NRLLEISPYM LSGRERALRP NRMYWRQGIY LNWSPEAYCL VGSEVLDNHP E SFLKITVP SCRKGCILLG QVVDHIDSLM EEWFPGLLEI DICGEGETLL KKWALYSFND GEEHQKILLD DLMKKAEEGD LL VNPDQPR LTIPISQIAP DLILADLPRN IMLNNDELEF EQAPEFLLGD GSFGSVYRAA YEGEEVAVKI FNKHTSLRLL RQE LVVLCH LHHPSLISLL AAGIRPRMLV MELASKGSLD RLLQQDKASL TRTLQHRIAL HVADGLRYLH SAMIIYRDLK PHNV LLFTL YPNAAIIAKI ADYGIAQYCC RMGIKTSEGT PGFRAPEVAR GNVIYNQQAD VYSFGLLLYD ILTTGGRIVE GLKFP NEFD ELEIQGKLPD PVKEYGCAPW PMVEKLIKQC LKENPQERPT SAQVFDILNS AELVCLTRRI LLPKNVIVEC MVATHH NSR NASIWLGCGH TDRGQLSFLD LNTEGYTSEE VADSRILCLA LVHLPVEKES WIVSGTQSGT LLVINTEDGK KRHTLEK MT DSVTCLYCNS FSKQSKQKNF LLVGTADGKL AIFEDKTVKL KGAAPLKILN IGNVSTPLMC LSESTNSTER NVMWGGCG T KIFSFSNDFT IQKLIETRTS QLFSYAAFSD SNIITVVVDT ALYIAKQNSP VVEVWDKKTE KLCGLIDCVH FLREVTVKE NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEI QSCLTVWDIN LPHEVQNLEK HIEVRKELAE KMRRTSVE

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: 2 / 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: 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}...

MacromoleculeName: 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
type: ligand / ID: 3 / Number of copies: 2 / Formula: 919
Molecular weightTheoretical: 553.587 Da
Chemical component information

ChemComp-919:
4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide

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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: 8
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: 67.53 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 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 reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 75005
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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