ArticleJournal of the American Chemical Society2013
Comprehensive experimental and computational analysis of binding energy hot spots at the NF-κB essential modulator/IKKβ protein-protein interface.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
- NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- The structure of a NEMO construct engineered for screening reveals novel determinants of inhibition.Structure (London, England : 1993) · 2025Article
- A conserved core region of the scaffold NEMO is essential for signal-induced conformational change and liquid-liquid phase separation.The Journal of biological chemistry · 2023Article
- A Conserved Core Region of the Scaffold NEMO is Essential for Signal-induced Conformational Change and Liquid-liquid Phase Separation.bioRxiv : the preprint server for biology · 2023Article
- FTMove: A Web Server for Detection and Analysis of Cryptic and Allosteric Binding Sites by Mapping Multiple Protein Structures.Journal of molecular biology · 2022Article
- Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth.Signal transduction and targeted therapy · 2022Article
- Benchmark Sets for Binding Hot Spot Identification in Fragment-Based Ligand Discovery.Journal of chemical information and modeling · 2020Article
- SPOTONE: Hot Spots on Protein Complexes with Extremely Randomized Trees via Sequence-Only Features.International journal of molecular sciences · 2020Article
- Article
- Why Some Targets Benefit from beyond Rule of Five Drugs.Journal of medicinal chemistry · 2019Article
- A Central Region of NF-κB Essential Modulator Is Required for IKKβ-Induced Conformational Change and for Signal Propagation.Biochemistry · 2019Article
- Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity.Nature communications · 2019Article
- Analysis of tractable allosteric sites in G protein-coupled receptors.Scientific reports · 2019Article
- The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface.Scientific reports · 2019Article
- Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation.PLoS biology · 2018Article
- Exploring the structural origins of cryptic sites on proteins.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Review
- Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition.PloS one · 2017Article
- A Synthetic Loop Replacement Peptide That Blocks Canonical NF-κB Signaling.Angewandte Chemie (International ed. in English) · 2016Article
- New Frontiers in Druggability.Journal of medicinal chemistry · 2015Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
We report a comprehensive analysis of binding energy hot spots at the protein-protein interaction (PPI) interface between nuclear factor kappa B (NF-κB) essential modulator (NEMO) and IκB kinase subunit β (IKKβ), an interaction that is critical for NF-κB pathway signaling, using experimental alanine scanning mutagenesis and also the FTMap method for computational fragment screening. The experimental results confirm that the previously identified NEMO binding domain (NBD) region of IKKβ contains the highest concentration of hot-spot residues, the strongest of which are W739, W741, and L742 (ΔΔG = 4.3, 3.5, and 3.2 kcal/mol, respectively). The region occupied by these residues defines a potentially druggable binding site on NEMO that extends for ~16 Å to additionally include the regions that bind IKKβ L737 and F734. NBD residues D738 and S740 are also important for binding but do not make direct contact with NEMO, instead likely acting to stabilize the active conformation of surrounding residues. We additionally found two previously unknown hot-spot regions centered on IKKβ residues L708/V709 and L719/I723. The computational approach successfully identified all three hot-spot regions on IKKβ. Moreover, the method was able to accurately quantify the energetic importance of all hot-spot residues involving direct contact with NEMO. Our results provide new information to guide the discovery of small-molecule inhibitors that target the NEMO/IKKβ interaction. They additionally clarify the structural and energetic complementarity between "pocket-forming" and "pocket-occupying" hot-spot residues, and further validate computational fragment mapping as a method for identifying hot spots at PPI interfaces.
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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.