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- EMDB-73495: Focused refinement map of LRRK2 APO state 2 -

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Basic information

Entry
Database: EMDB / ID: EMD-73495
TitleFocused refinement map of LRRK2 APO state 2
Map data
Sample
  • Organelle or cellular component: Leucine rich repeat LRRK2
KeywordsLRRK2 / Kinase / Gtpases / HYDROLASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.82 Å
AuthorsVillagran Suarez A / Bodrug T / Leschziner A
Funding support United States, 1 items
OrganizationGrant numberCountry
Aligning Science Across Parkinsons (ASAP)ASAP-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 21, 2025-
Header (metadata) releaseAug 19, 2026-
Map releaseAug 19, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73495.png

Downloads & links

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Map

FileDownload / File: emd_73495.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.)
0.94 Å/pix.
x 288 pix.
= 269.28 Å		0.94 Å/pix.
x 288 pix.
= 269.28 Å		0.94 Å/pix.
x 288 pix.
= 269.28 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.935 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.127
Minimum - Maximum-0.4922431 - 0.7908657
Average (Standard dev.)0.00016916468 (±0.014608987)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 269.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_73495_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_73495_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Leucine rich repeat LRRK2

EntireName: Leucine rich repeat LRRK2
Components
  • Organelle or cellular component: Leucine rich repeat LRRK2

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Supramolecule #1: Leucine rich repeat LRRK2

SupramoleculeName: Leucine rich repeat LRRK2 / type: organelle_or_cellular_component / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / 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: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.82 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 96134
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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