ArticleScientific reports2019
Understanding allosteric interactions in hMLKL protein that modulate necroptosis and its inhibition.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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.
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.
Who cites it
12 citing papers in PubMed.
- Ferroptosis in Cancer: Mechanism and Therapeutic Potential.International journal of molecular sciences · 2025Review
- MLKL, a new actor of UVB-induced apoptosis in human diploid dermal fibroblasts.Cell death discovery · 2024Article
- RIP3 in Necroptosis: Underlying Contributions to Traumatic Brain Injury.Neurochemical research · 2024Review
- GSDMD-mediated pyroptosis in retinal vascular inflammatory diseases: a review.International ophthalmology · 2023Review
- From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors.Journal of medicinal chemistry · 2023Review
- Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures.Frontiers in pharmacology · 2023Article
- Effect of Size and Concentration of Copper Nanoparticles on the Antimicrobial Activity inNanomaterials (Basel, Switzerland) · 2022Article
- Necroptosis-Mediated eCIRP Release in Sepsis.Journal of inflammation research · 2022Article
- Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis.Molecules (Basel, Switzerland) · 2021Article
- Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.Nature communications · 2021Article
- Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Lytic cell death in metabolic liver disease.Journal of hepatology · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mixed Lineage Kinase domain-Like (MLKL), a key player in necroptosis, is a multi-domain protein with an N-terminal 4 helical bundle (4HB) and a pseudokinase domain (PsK) connected by brace helices. Phosphorylation of PsK domain of MLKL is a key step towards oligomerization of 4HB domain that causes cell death. Necrosulfonamide (NSA) binds to the 4HB domain of MLKL to inhibit necroptosis. To understand the molecular details of MLKL function and it's inhibition, we have performed a molecular dynamic study on hMLKL protein in apo, phosphorylated and NSA-bound states for a total 3 μs simulation time. Our simulations show increased inter-domain flexibility, increased rigidification of the activation loop and increased alpha helical content in the brace helix region revealing a form of monomeric hMLKL necessary for oligomerization upon phosphorylation as compared to apo state. NSA binding disrupts this activated form and causes two main effects on hMLKL conformation: (1) locking of the relative orientation of 4HB and PsK domains by the formation of several new interactions and (2) prevention of key 4HB residues to participate in cross-linking for oligomer formation. This new understanding of the effect of hMLKL conformations on phosphorylation and NSA binding suggest new avenues for designing effective allosteric inhibitors of hMLKL.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.