ArticleThe Journal of biological chemistry2013
The structural basis for endotoxin-induced allosteric regulation of the Toll-like receptor 4 (TLR4) innate immune receptor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 62 citations in OpenAlex.
- Integrative Bioinformatics Prioritizes theBiology · 2026Article
- Structural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes.Nature communications · 2025Article
- The Role of Natural Products from Herbal Medicine in TLR4 Signaling for Colorectal Cancer Treatment.Molecules (Basel, Switzerland) · 2024Review
- Therapeutic Targeting of TLR4 for Inflammation, Infection, and Cancer: A Perspective for Disaccharide Lipid A Mimetics.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Commensal gut microbiota-based strategies for oral delivery of therapeutic proteins.Trends in pharmacological sciences · 2022Review
- Lipid A Mimetics Based on Unnatural Disaccharide Scaffold as Potent TLR4 Agonists for Prospective Immunotherapeutics and Adjuvants.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Adaptation and Cryptic Pseudogenization in Penguin Toll-Like Receptors.Molecular biology and evolution · 2022Article
- Full-Atom Model of the Agonist LPS-Bound Toll-like Receptor 4 Dimer in a Membrane Environment.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.Frontiers in immunology · 2021Article
- Shortening the Lipid A Acyl Chains ofVaccines · 2020Article
- Recent Advances in Lipopolysaccharide Recognition Systems.International journal of molecular sciences · 2020Review
- Key residues in TLR4-MD2 tetramer formation identified by free energy simulations.PLoS computational biology · 2019Article
- Toll-Like Receptor Evolution in Birds: Gene Duplication, Pseudogenization, and Diversifying Selection.Molecular biology and evolution · 2018Article
- Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides.Nature communications · 2018Article
- Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists.Journal of chemical information and modeling · 2018Article
- Atomistic Scale Effects of Lipopolysaccharide Modifications on Bacterial Outer Membrane Defenses.Biophysical journal · 2018Article
- Article
- Computational Insight Into the Structural Organization of Full-Length Toll-Like Receptor 4 Dimer in a Model Phospholipid Bilayer.Frontiers in immunology · 2018Article
- Structure-Activity Relationship in TLR4 Mutations: Atomistic Molecular Dynamics Simulations and Residue Interaction Network Analysis.Scientific reports · 2017Article
- Prepartal Energy Intake Alters Blood Polymorphonuclear Leukocyte Transcriptome During the Peripartal Period in Holstein Cows.Bioinformatics and biology insights · 2017Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
As part of the innate immune system, Toll-like receptor 4 (TLR4) recognizes bacterial cell surface lipopolysaccharide (LPS) by forming a complex with a lipid-binding co-receptor, MD-2. In the presence of agonist, TLR4·MD-2 dimerizes to form an active receptor complex, leading to initiation of intracellular inflammatory signals. TLR4 is of great biomedical interest, but its pharmacological manipulation is complicated because even subtle variations in the structure of LPS can profoundly impact the resultant immunological response. Here, we use atomically detailed molecular simulations to gain insights into the nature of the molecular signaling mechanism. We first demonstrate that MD-2 is extraordinarily flexible. The "clamshell-like" motions of its β-cup fold enable it to sensitively match the volume of its hydrophobic cavity to the size and shape of the bound lipid moiety. We show that MD-2 allosterically transmits this conformational plasticity, in a ligand-dependent manner, to a phenylalanine residue (Phe-126) at the cavity mouth previously implicated in TLR4 activation. Remarkably, within the receptor complex, we observe spontaneous transitions between active and inactive signaling states of Phe-126, and we confirm that Phe-126 is indeed the "molecular switch" in endotoxic signaling.
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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.