Evidence map›Paper›PMID 42599991›Full record

ArticleScience advances2026

Ligand-tuned extracellular domain dynamics are correlated with signaling states in an adhesion GPCR.

Kristina Cechova, Sumit J Bandekar, Szymon P Kordon, Max Foroutan, Katherine Leon, Gracie Siffer, Michael R Schamber, Maria Luiso, Demet Araç, Reza Vafabakhsh

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Kristina CechovaDepartment of Molecular Biosciences, Northwestern University, Evanston, IL, USA.ORCID 0000-0002-0955-1795
Sumit J BandekarDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.ORCID 0000-0003-2728-7366
Szymon P KordonDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.ORCID 0000-0002-3770-0743
Max ForoutanDepartment of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
Katherine LeonDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.ORCID 0000-0002-0870-5000
Gracie SifferDepartment of Molecular Biosciences, Northwestern University, Evanston, IL, USA.ORCID 0009-0007-1441-8394
Michael R SchamberDepartment of Molecular Biosciences, Northwestern University, Evanston, IL, USA.ORCID 0000-0003-1261-1995
Maria LuisoDepartment of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
Demet AraçDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.ORCID 0000-0002-5444-5799
Reza VafabakhshDepartment of Molecular Biosciences, Northwestern University, Evanston, IL, USA.ORCID 0000-0001-8384-3203

Funding

Molecular Biophysics Training Program at Northwestern UniversityT32GM140995 · NIGMS · NORTHWESTERN UNIVERSITY · PI Heather Wendy Pinkett, Reza Vafabakhsh · 2021 to 2026
$2.5M
Structural and Functional Studies of Cell-Adhesion ReceptorsR35GM148412 · NIGMS · UNIVERSITY OF CHICAGO · PI Demet Arac-Ozkan · 2023 to 2026
$2.2M
Quantitative analysis of metabotropic glutamate receptor activation and modulationR01GM140272 · NIGMS · NORTHWESTERN UNIVERSITY · PI VAFABAKHSH, REZA · 2020 to 2024
$1.7M
Structural and Functional Characterization of CELSR-subfamily adhesion G protein-coupled receptorsK99GM157487 · NIGMS · UNIVERSITY OF CHICAGO · PI Sumit Bandekar · 2025 to 2026
$218k
Structure, Function, and Antibody-based Modulation of GPR126: Regulation of an Adhesion GPCR by its Extracellular RegionF32GM142266 · NIGMS · UNIVERSITY OF CHICAGO · PI BANDEKAR, SUMIT · 2021 to 2023
$205k
NIGMS NIH HHS F32 GM142266NIGMS NIH HHS K99 GM157487NIGMS NIH HHS R01 GM140272NIGMS NIH HHS R35 GM148412NIGMS NIH HHS T32 GM140995
6 · The paper itself

Abstract

Adhesion G protein-coupled receptors (aGPCRs) transduce signals via engagement of their large extracellular regions (ECRs) with adhesion partners. ADGRG6 (GPR126) is an aGPCR vital for the development of multiple organs and myelination. ECR conformational dynamics of ADGRG6 has been shown to modulate aGPCR signaling and in vivo function. Yet, how adhesion partners regulate ECR conformational dynamics is poorly understood. Here, we studied activation of ADGRG6 using single-molecule FRET (smFRET) and intracellular signaling assays. We reveal that the ADGRG6 ECR dynamically transitions between three conformational states. Covalently locking the ECR in the closed conformation traps the receptor in a low-activity state. Agonist binding physically restricts the ECR to only access states associated with higher activity. This detailed mechanistic insight into ADGRG6 allosteric regulation by ECR dynamics offers avenues for targeted therapeutic development.

Indexed as

Receptors, G-Protein-CoupledSignal TransductionAllosteric RegulationFluorescence Resonance Energy TransferHumansLigandsProtein BindingProtein ConformationProtein DomainsLigandsReceptors, G-Protein-Coupled

Identifiers

PMID42599991
PMCPMC13475471

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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 Socratic graph.