Evidence map›Paper›PMID 42575089›Full record

ArticleCell2026

The structural basis for LRRK2's activation and autoinhibition.

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 and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors.

Amalia Villagran SuarezDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Kathryn S HatchDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Tatyana BodrugDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Wei GaiDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Katherine J SurridgeDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Elizabeth MoussikhinaDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Kendrick H V NguyenDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Marta Sanz-MurilloDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Robert CallahanDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Erica XiongDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Delisa RamosDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Lawrence ZhuDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
Verena DedererInstitute of Pharmaceutical Chemistry and Structural Genomics Consortium, Goethe-University Frankfurt am Main, Frankfurt, Germany.
Sebastian MatheaInstitute of Pharmaceutical Chemistry and Structural Genomics Consortium, Goethe-University Frankfurt am Main, Frankfurt, Germany.
Janet IwasaDepartment of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA.
Stefan KnappInstitute of Pharmaceutical Chemistry and Structural Genomics Consortium, Goethe-University Frankfurt am Main, Frankfurt, Germany; LRRK2 Investigative Therapeutics Exchange (LITE), New York, NY 10120, USA.
Kevan M ShokatDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; LRRK2 Investigative Therapeutics Exchange (LITE), New York, NY 10120, USA.
Samara L Reck-PetersonDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92093, USA; LRRK2 Investigative Therapeutics Exchange (LITE), New York, NY 10120, USA. Electronic address: slr4003@med.cornell.edu.
Andres E LeschzinerDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA; LRRK2 Investigative Therapeutics Exchange (LITE), New York, NY 10120, USA. Electronic address: ale4009@med.cornell.edu.

Funding

Molecular Biophysics Training Grant at UC San DiegoT32GM139795 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Galia Debelouchina, ELIZABETH A. KOMIVES · 2021 to 2026
$3.0M
Howard Hughes Medical InstituteNIGMS NIH HHS T32 GM139795
6 · The paper itself

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 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.

Indexed as

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2AnimalsCryoelectron MicroscopyGuanosine DiphosphateGuanosine TriphosphateHumansModels, MolecularMutationParkinson DiseaseGuanosine DiphosphateGuanosine TriphosphateLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, humanactivationautoinhibitioncryo-EMG2019SGTPasekinaseLRRK2Parkinson’s diseaseR1441CR1441H

Identifiers

PMID42575089
PMCPMC13632595

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.