Evidence map›Paper›PMID 39662679›Full record

ArticleJournal of molecular biology2025

Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network.

Claire H Woodward, Shahlo O Solieva, Daniel Hwang, Viviane S De Paula, Charina S Fabilane, Michael C Young, Tony Trent, Ella C Teeley, Ananya Majumdar, Jamie B Spangler and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of molecular biology, 2025. 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

5 · Who and what money

Authors and funding

12 authors.

Claire H WoodwardDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Shahlo O SolievaDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Daniel HwangDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Viviane S De PaulaDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Charina S FabilaneTranslational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA.
Michael C YoungDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Tony TrentDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Ella C TeeleyDepartment of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Ananya MajumdarBiomolecular NMR Center, Johns Hopkins University, Baltimore, MD, USA.
Jamie B SpanglerTranslational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Gregory R BowmanDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Nikolaos G SgourakisDepartment of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: nikolaos.sgourakis@pennmedicine.upenn.edu.

Funding

An integrative structural biology approach to understanding metabolite recognition by cellular receptorsR35GM125034 · NIGMS · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI SGOURAKIS, NIKOLAOS · 2017 to 2025
$4.7M
Molecular mechanism of antigen editing by Class-I MHC ChaperonesR01AI143997 · NIAID · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI SGOURAKIS, NIKOLAOS · 2019 to 2023
$4.0M
Structural biology and molecular biophysics training programT32GM132039 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI Ben E. Black, Elizabeth Rhoades · 2019 to 2026
$3.3M
NextGen - CHOPOT2CA278687 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI JOHN M MARIS · 2022 to 2026
$2.7M
Biomimetic Matrix for Ex Vivo and In Vivo Activation of T CellsR01EB029341 · NIBIB · JOHNS HOPKINS UNIVERSITY · PI MAO, HAI-QUAN, SCHNECK, JONATHAN P · 2020 to 2023
$1.9M
Understanding and controlling protein energy landscapes by combining simulations and experimentsR35GM152085 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI Gregory Bowman · 2024 to 2026
$1.2M
Cancer Research UK CGCAT F-2021/100002NCI NIH HHS OT2 CA278687NIAID NIH HHS R01 AI143997NIBIB NIH HHS R01 EB029341NIGMS NIH HHS R35 GM125034NIGMS NIH HHS R35 GM152085NIGMS NIH HHS T32 GM132039
6 · The paper itself

Abstract

Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.

Indexed as

Interleukin-2Signal TransductionAllosteric RegulationBinding SitesHumansMolecular Dynamics SimulationMutationProtein BindingProtein ConformationReceptors, Interleukin-2T-LymphocytesIL2 protein, humanInterleukin-2Receptors, Interleukin-2conformational exchangeinterleukin-2molecular dynamics simulationsnuclear magnetic resonance spectroscopyT cells

Identifiers

PMID39662679
PMCPMC12077578

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.