ArticlePloS one2012
Structure-based rational design of a Toll-like receptor 4 (TLR4) decoy receptor with high binding affinity for a target protein.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- In vitro and in silico studies of 7'',8''-buddlenol D anti-inflammatory lignans from Carallia brachiata as p38 MAP kinase inhibitors.Scientific reports · 2023Article
- Exploration of the mechanism by which Huangqi Guizhi Wuwu decoction inhibits Lps-induced inflammation by regulating macrophage polarization based on network pharmacology.BMC complementary medicine and therapies · 2023Article
- Human-Based Immune Responsive In Vitro Infection Models for Validation of Novel TLR4 Antagonists Identified by Computational Discovery.Microorganisms · 2022Article
- Allergens and their associated small molecule ligands-their dual role in sensitization.Allergy · 2021Review
- TLR4-Targeting Therapeutics: Structural Basis and Computer-Aided Drug Discovery Approaches.Molecules (Basel, Switzerland) · 2020Review
- Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus.Molecular neurobiology · 2019Article
- Fast Green FCF Attenuates Lipopolysaccharide-Induced Depressive-Like Behavior and Downregulates TLR4/Myd88/NF-κB Signal Pathway in the Mouse Hippocampus.Frontiers in pharmacology · 2019Article
- Mapping protein selectivity landscapes using multi-target selective screening and next-generation sequencing of combinatorial libraries.Nature communications · 2018Article
- Interfering with the high-affinity interaction between wheat amylase trypsin inhibitor CM3 and toll-like receptor 4: in silico and biosensor-based studies.Scientific reports · 2017Article
- TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis.Vaccines · 2017Review
- Contributions and Future Directions for Structural Biology in the Study of Allergens.International archives of allergy and immunology · 2017Review
- NextGen protein design.Biochemical Society transactions · 2013Review
- Increasing affinity of interferon-γ receptor 1 to interferon-γ by computer-aided design.BioMed research international · 2013Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Repeat proteins are increasingly attracting much attention as alternative scaffolds to immunoglobulin antibodies due to their unique structural features. Nonetheless, engineering interaction interface and understanding molecular basis for affinity maturation of repeat proteins still remain a challenge. Here, we present a structure-based rational design of a repeat protein with high binding affinity for a target protein. As a model repeat protein, a Toll-like receptor4 (TLR4) decoy receptor composed of leucine-rich repeat (LRR) modules was used, and its interaction interface was rationally engineered to increase the binding affinity for myeloid differentiation protein 2 (MD2). Based on the complex crystal structure of the decoy receptor with MD2, we first designed single amino acid substitutions in the decoy receptor, and obtained three variants showing a binding affinity (K(D)) one-order of magnitude higher than the wild-type decoy receptor. The interacting modes and contributions of individual residues were elucidated by analyzing the crystal structures of the single variants. To further increase the binding affinity, single positive mutations were combined, and two double mutants were shown to have about 3000- and 565-fold higher binding affinities than the wild-type decoy receptor. Molecular dynamics simulations and energetic analysis indicate that an additive effect by two mutations occurring at nearby modules was the major contributor to the remarkable increase in the binding affinities.
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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.