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- EMDB-73338: C-terminal LRRK2 bound to C12 DARPin -

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Basic information

Entry
Database: EMDB / ID: EMD-73338
TitleC-terminal LRRK2 bound to C12 DARPin
Map data
Sample
  • Complex: C-terminal LRRK2 bound to C12 DARPin
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
    • Protein or peptide: C12 DARPin
KeywordsKinase / Complex / DARPins / PROTEIN BINDING
Function / homology
Function and homology information


regulation of neuron maturation / 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 / tangential migration from the subventricular zone to the olfactory bulb / regulation of cell projection organization ...regulation of neuron maturation / 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 / tangential migration from the subventricular zone to the olfactory bulb / regulation of cell projection organization / regulation of dopamine receptor signaling pathway / regulation of ER to Golgi vesicle-mediated transport / GTP-dependent protein kinase activity / regulation of SNARE complex assembly / regulation of neuroblast proliferation / protein localization to endoplasmic reticulum exit site / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / : / peroxidase inhibitor activity / positive regulation of dopamine receptor signaling pathway / amphisome / regulation of synaptic vesicle transport / : / regulation of CAMKK-AMPK signaling cascade / striatum development / negative regulation of autophagosome assembly / co-receptor binding / positive regulation of microglial cell activation / olfactory bulb development / regulation of retrograde transport, endosome to Golgi / negative regulation of GTPase activity / cellular response to curcumin / regulation of locomotion / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / cytoplasmic side of mitochondrial outer membrane / endoplasmic reticulum organization / regulation of cAMP/PKA signal transduction / negative regulation of excitatory postsynaptic potential / multivesicular body, internal vesicle / neuron projection arborization / regulation of dendritic spine morphogenesis / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / mitochondrion localization / protein localization to mitochondrion / cellular response to dopamine / negative regulation of protein processing / Wnt signalosome / positive regulation of protein autoubiquitination / exploration behavior / GTP metabolic process / regulation of reactive oxygen species metabolic process / regulation of canonical Wnt signaling pathway / lysosome organization / syntaxin-1 binding / positive regulation of programmed cell death / negative regulation of macroautophagy / PTK6 promotes HIF1A stabilization / Golgi-associated vesicle / clathrin binding / regulation of synaptic vesicle exocytosis / locomotory exploration behavior / Golgi organization / regulation of mitochondrial fission / intracellular distribution of mitochondria / Lewy body / protein kinase A binding / canonical Wnt signaling pathway / microvillus / neuromuscular junction development / autolysosome / endoplasmic reticulum exit site / Rho protein signal transduction / determination of adult lifespan / MAP kinase kinase kinase activity / JNK cascade / regulation of synaptic vesicle endocytosis / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of synaptic transmission, glutamatergic / presynaptic cytosol / cellular response to manganese ion / phagocytic vesicle / neuron projection morphogenesis / positive regulation of autophagy / dendrite cytoplasm / excitatory postsynaptic potential / positive regulation of protein ubiquitination / cellular response to starvation / GTPase activator activity / calcium-mediated signaling / mitochondrion organization / SNARE binding / negative regulation of neuron projection development / cellular response to reactive oxygen species / trans-Golgi network / regulation of protein stability / regulation of membrane potential / tubulin binding / regulation of autophagy
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 / Leucine-rich repeat domain superfamily / Rab subfamily of small GTPases / 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: 3.6 Å
AuthorsSanz-Murillo M / Leschziner A
Funding support United States, 1 items
OrganizationGrant numberCountry
Other privateASAP-000519 United States
CitationJournal: Cell / Year: 2026
Title: The structural basis for LRRK2's activation and autoinhibition.
Authors: Amalia Villagran Suarez / Kathryn S Hatch / Tatyana Bodrug / Wei Gai / Katherine J Surridge / Elizabeth Moussikhina / Kendrick H V Nguyen / Marta Sanz-Murillo / Robert Callahan / Erica Xiong ...Authors: Amalia Villagran Suarez / Kathryn S Hatch / Tatyana Bodrug / Wei Gai / Katherine J Surridge / Elizabeth Moussikhina / Kendrick H V Nguyen / Marta Sanz-Murillo / Robert Callahan / Erica Xiong / Delisa Ramos / Lawrence Zhu / Verena Dederer / Sebastian Mathea / Janet Iwasa / Stefan Knapp / Kevan M Shokat / Samara L Reck-Peterson / Andres E Leschziner /
Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic ...Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the guanosine diphosphate (GDP)-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.
History
DepositionOct 15, 2025-
Header (metadata) releaseAug 12, 2026-
Map releaseAug 12, 2026-
UpdateAug 19, 2026-
Current statusAug 19, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73338.png

Downloads & links

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Map

FileDownload / File: emd_73338.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 288 pix.
= 334.08 Å		1.16 Å/pix.
x 288 pix.
= 334.08 Å		1.16 Å/pix.
x 288 pix.
= 334.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.16 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.14
Minimum - Maximum-71.407020000000003 - 89.698179999999994
Average (Standard dev.)0.0006055782 (±0.92999125)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 334.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : C-terminal LRRK2 bound to C12 DARPin

EntireName: C-terminal LRRK2 bound to C12 DARPin
Components
  • Complex: C-terminal LRRK2 bound to C12 DARPin
    • Protein or peptide: Leucine-rich repeat serine/threonine-protein kinase 2
    • Protein or peptide: C12 DARPin

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Supramolecule #1: C-terminal LRRK2 bound to C12 DARPin

SupramoleculeName: C-terminal LRRK2 bound to C12 DARPin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 156 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 286.462781 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSER ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLI EVCPGTMQSL MGPQDVGNDW EVLGVHQLIL KMLTVHNASV NLSVIGLKTL DLLLTSGKIT LLILDEESDI F MLIFDAMH ...String:
MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSER 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 FPKNYMSQYF 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 FLREVMVKE 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: C12 DARPin

MacromoleculeName: C12 DARPin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 14.348062 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MRGSHHHHHH HHGSDLGKKL LEAAMSGQDD EVRILMANGA DVNTQDQFGL TPLHLAAIEG HLEIVEVLLK TGADVNALDW VGTTPLHLA AYVGHLEIVE VLLKHGADVN EDIAEVLQKA AKLNDYKDDD DK

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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

Concentration0.68 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMSodium ChlorideNaCl2
2.5 mMMagnesium ChlorideMgCl2
0.5 mMTCEP
5.0 %Glycerol
20.0 uMGDP
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated defocus min: 2.5 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 36.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6vp7

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1) / Number images used: 392016
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.1)

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Atomic model buiding 1

Initial modelPDB ID:

6vp7


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9yqk:
C-terminal LRRK2 bound to C12 DARPin

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