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- EMDB-47006: Structure of the C-terminal half of LRRK2 bound to RN277 (Type-II... -

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Basic information

Entry
Database: EMDB / ID: EMD-47006
TitleStructure of the C-terminal half of LRRK2 bound to RN277 (Type-II inhibitor)
Map dataConsensus refinement
Sample
  • Complex: C-terminal half of LRRK2 bound to RN277
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
    • Protein or peptide: E11 DARPin
  • Ligand: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{(3M)-3-[2-chloro-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}urea
KeywordsGTPase / Kinase / inhibitors / PROTEIN BINDING
Function / homology
Function and homology information


caveola neck / : / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / Wnt signalosome assembly / negative regulation of motile cilium 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 ...caveola neck / : / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / Wnt signalosome assembly / negative regulation of motile cilium 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 CAMKK-AMPK signaling cascade / co-receptor binding / negative regulation of GTPase activity / regulation of dopamine receptor signaling pathway / cellular response to curcumin / positive regulation of microglial cell activation / regulation of retrograde transport, endosome to Golgi / regulation of neuron maturation / cytoplasmic side of mitochondrial outer membrane / negative regulation of autophagosome assembly / positive regulation of synaptic vesicle endocytosis / olfactory bulb development / JUN kinase kinase kinase activity / regulation of cAMP/PKA signal transduction / multivesicular body, internal vesicle / negative regulation of excitatory postsynaptic potential / neuron projection arborization / striatum development / 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 / negative regulation of protein processing / Wnt signalosome / 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 / Golgi-associated vesicle / PTK6 promotes HIF1A stabilization / negative regulation of macroautophagy / clathrin binding / lysosome organization / regulation of mitochondrial fission / Lewy body / regulation of locomotion / protein kinase A binding / intracellular distribution of mitochondria / regulation of synaptic vesicle exocytosis / Golgi organization / neuromuscular junction development / microvillus / autolysosome / exploration behavior / locomotory exploration behavior / endoplasmic reticulum exit site / negative regulation of Notch signaling pathway / MAP kinase kinase kinase activity / regulation of synaptic vesicle endocytosis / canonical Wnt signaling pathway / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of synaptic transmission, glutamatergic / Rho protein signal transduction / presynaptic cytosol / neuron projection morphogenesis / phagocytic vesicle / cellular response to manganese ion / JNK cascade / positive regulation of autophagy / dendrite cytoplasm / cellular response to starvation / positive regulation of protein ubiquitination / GTPase activator activity / determination of adult lifespan / regulation of autophagy / SNARE binding / cellular response to reactive oxygen species / mitochondrion organization / trans-Golgi network / excitatory postsynaptic potential / calcium-mediated signaling / regulation of membrane potential / regulation of protein stability / tubulin binding
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 / 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 / Serine/Threonine protein kinases, catalytic domain / WD40-repeat-containing domain superfamily / 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) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsSanz-Murillo M / Leschziner A
Funding support United States, 1 items
OrganizationGrant numberCountry
Michael J. Fox FoundationASAP-000519 United States
CitationJournal: Sci Adv / Year: 2025
Title: Type II kinase inhibitors that target Parkinson's disease-associated LRRK2.
Authors: Nicolai D Raig / Katherine J Surridge / Marta Sanz-Murillo / Verena Dederer / Andreas Krämer / Martin P Schwalm / Nicholas M Lattal / Lewis Elson / Deep Chatterjee / Sebastian Mathea / ...Authors: Nicolai D Raig / Katherine J Surridge / Marta Sanz-Murillo / Verena Dederer / Andreas Krämer / Martin P Schwalm / Nicholas M Lattal / Lewis Elson / Deep Chatterjee / Sebastian Mathea / Thomas Hanke / Andres E Leschziner / Samara L Reck-Peterson / Stefan Knapp /
Abstract: Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have ...Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors. We designed these inhibitors with a combinatorial chemistry approach fusing selective LRRK2 type I and promiscuous type II inhibitors using iterative cycles of synthesis supported by structural biology and activity testing. Our lead compounds are selective and potent toward both LRRK2 and LRRK1, a close relative of LRRK2. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive LRRK2 kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation and expand the potential therapeutic options for PD.
History
DepositionSep 13, 2024-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47006.png

Downloads & links

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Map

FileDownload / File: emd_47006.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationConsensus refinement
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 400 pix.
= 374. Å		0.94 Å/pix.
x 400 pix.
= 374. Å		0.94 Å/pix.
x 400 pix.
= 374. Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.935 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.111
Minimum - Maximum-1.2406037 - 1.5275391
Average (Standard dev.)-0.00038993882 (±0.014281598)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 374.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_47006_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_47006_half_map_2.map
Projections & Slices
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Sample components

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Entire : C-terminal half of LRRK2 bound to RN277

EntireName: C-terminal half of LRRK2 bound to RN277
Components
  • Complex: C-terminal half of LRRK2 bound to RN277
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
    • Protein or peptide: E11 DARPin
  • Ligand: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{(3M)-3-[2-chloro-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}urea

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Supramolecule #1: C-terminal half of LRRK2 bound to RN277

SupramoleculeName: C-terminal half of LRRK2 bound to RN277 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 137 KDa

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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: 136.174781 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: NRMKLMIVGN TGSGKTTLLQ QLMKTKKSDL GMQSATVGID VKDWPIQIRD KRKRDLVLNV WDFAGREEFY STHPHFMTQR ALYLAVYDL SKGQAEVDAM KPWLFNIKAR ASSSPVILVG THLDVSDEKQ RKACMSKITK ELLNKRGFPA IRDYHFVNAT E ESDALAKL ...String:
NRMKLMIVGN TGSGKTTLLQ QLMKTKKSDL GMQSATVGID VKDWPIQIRD KRKRDLVLNV WDFAGREEFY STHPHFMTQR ALYLAVYDL SKGQAEVDAM KPWLFNIKAR ASSSPVILVG THLDVSDEKQ RKACMSKITK ELLNKRGFPA IRDYHFVNAT E ESDALAKL RKTIINESLN FKIRDQLVVG QLIPDCYVEL EKIILSERKN VPIEFPVIDR KRLLQLVREN QLQLDENELP HA VHFLNES GVLLHFQDPA LQLSDLYFVE PKWLCKIMAQ ILTVKVEGCP KHPKGIISRR DVEKFLSKKR KFPKNYMSQY FKL LEKFQI ALPIGEEYLL VPSSLSDHRP VIELPHCENS EIIIRLYEMP YFPMGFWSRL INRLLEISPY MLSGRERALR PNRM YWRQG IYLNWSPEAY CLVGSEVLDN HPESFLKITV PSCRKGCILL GQVVDHIDSL MEEWFPGLLE IDICGEGETL LKKWA LYSF NDGEEHQKIL LDDLMKKAEE GDLLVNPDQP RLTIPISQIA PDLILADLPR NIMLNNDELE FEQAPEFLLG DGSFGS VYR AAYEGEEVAV KIFNKHTSLR LLRQELVVLC HLHHPSLISL LAAGIRPRML VMELASKGSL DRLLQQDKAS LTRTLQH RI ALHVADGLRY LHSAMIIYRD LKPHNVLLFT LYPNAAIIAK IADYGIAQYC CRMGIKTSEG TPGFRAPEVA RGNVIYNQ Q ADVYSFGLLL YDILTTGGRI VEGLKFPNEF DELEIQGKLP DPVKEYGCAP WPMVEKLIKQ CLKENPQERP TSAQVFDIL NSAELVCLTR RILLPKNVIV ECMVATHHNS RNASIWLGCG HTDRGQLSFL DLNTEGYTSE EVADSRILCL ALVHLPVEKE SWIVSGTQS GTLLVINTED GKKRHTLEKM TDSVTCLYCN SFSKQSKQKN FLLVGTADGK LAIFEDKTVK LKGAAPLKIL N IGNVSTPL MCLSESTNST ERNVMWGGCG TKIFSFSNDF TIQKLIETRT SQLFSYAAFS DSNIITVVVD TALYIAKQNS PV VEVWDKK TEKLCGLIDC VHFLREVMVK ENKESKHKMS YSGRVKTLCL QKNTALWIGT GGGHILLLDL STRRLIRVIY NFC NSVRVM MTAQLGSLKN VMLVLGYNRK NTEGTQKQKE IQSCLTVWDI NLPHEVQNLE KHIEVRKELA EKMRRTSVE

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

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Macromolecule #2: E11 DARPin

MacromoleculeName: E11 DARPin / type: protein_or_peptide / ID: 2
Details: Some loops are missing due to the lack of cryo-EM density
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 19.766912 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MRGSHHHHHH HHGSDLGKKL LEAARAGQDD EVRILMANGA DVNATDEAGV TPLHLAADSG HLEIVEVLLK TGADVNAWDH YGFTPLHLA AHVGHLEIVE VLLKAGADVN AQDHAGWTPL HLAALYGHLE IVEVLLKHGA DVNAQDMWGE TPFDLAIDNG N EDIAEVLQ KAAKLNDYKD DDDK

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Macromolecule #3: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{(3M)-3-[2...

MacromoleculeName: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{(3M)-3-[2-chloro-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}urea
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1A7Q
Molecular weightTheoretical: 585.099 Da

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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

Concentration616.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMSodium ChlorideNaCl
2.5 mMMagnesium ChlorideMgCl2
5.0 %GlycerolGlyOH
20.0 uMGDP
0.5 mMTCEP
GridModel: UltrAuFoil R2/2 / Material: GOLD / Mesh: 200 / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV / Details: Blot time 4s Blot force 5 Waiting time 20s.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 13972 / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.3) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6vp7

Final reconstructionAlgorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 226172
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6vp7


Chain - Chain ID: A / Chain - Residue range: 1333-2527 / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9dmi:
Structure of the C-terminal half of LRRK2 bound to RN277 (Type-II inhibitor)

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