ArticleJournal of the American Chemical Society2006
NMR distinction of single- and multiple-mode binding of small-molecule protein ligands.
Article in Journal of the American Chemical Society, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Characterization of a CYP107 family vitamin DArchives of biochemistry and biophysics · 2026Article
- NMR-driven structure-based drug discovery by unveiling molecular interactions.Communications chemistry · 2025Review
- Recognition of single-stranded nucleic acids by small-molecule splicing modulators.Nucleic acids research · 2021Article
- Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation.International journal of molecular sciences · 2021Article
- The role of NMR in leveraging dynamics and entropy in drug design.Journal of biomolecular NMR · 2020Article
- A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery.Molecules (Basel, Switzerland) · 2020Review
- Structural equilibrium underlying ligand-dependent activation of βNature chemical biology · 2020Article
- Endosidin2-14 Targets the Exocyst Complex in Plants and Fungal Pathogens to Inhibit Exocytosis.Plant physiology · 2019Article
- Solution NMR Studies of an Alternative Mode of Sin3 Engagement by the Sds3 Subunit in the Histone Deacetylase-Associated Sin3L/Rpd3L Corepressor Complex.Journal of molecular biology · 2015Article
- An alternate binding site for PPARγ ligands.Nature communications · 2014Article
- Fragment-based drug discovery using NMR spectroscopy.Journal of biomolecular NMR · 2013Review
- Domain organization of XAF1 and the identification and characterization of XIAP(RING) -binding domain of XAF1.Protein science : a publication of the Protein Society · 2012Article
- Characterizing the N- and C-terminal Small ubiquitin-like modifier (SUMO)-interacting motifs of the scaffold protein DAXX.The Journal of biological chemistry · 2011Article
- Structure of the VP16 transactivator target in the Mediator.Nature structural & molecular biology · 2011Article
- Binding site identification and structure determination of protein-ligand complexes by NMR a semiautomated approach.Methods in enzymology · 2011Article
- High-field solution NMR spectroscopy as a tool for assessing protein interactions with small molecule ligands.Journal of pharmaceutical sciences · 2008Review
- The role of higher CO-multipole moments in understanding the dynamics of photodissociated carbonmonoxide in myoglobin.Biophysical journal · 2008Article
- Mapping of the auto-inhibitory interactions of protein kinase R by nuclear magnetic resonance.Journal of molecular biology · 2006Article
- Identification of individual protein-ligand NOEs in the limit of intermediate exchange.Journal of biomolecular NMR · 2006Article
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3 authors.
Funding
Abstract
Identifying and characterizing small-molecule inhibitors of protein-protein interactions is of high interest for drug discovery and for chemical genetics studies of biological pathways. Very often, initial hits or first-generation compounds have low micromolar dissociation constants and cause line broadening in NMR spectra. It is very important for subsequent structure-based compound optimization to know if this line broadening is caused by intermediate exchange of the dissociation kinetics only or in addition by multiple binding modes. Here, we present an approach of how to distinguish these two situations and demonstrate its experimental application. Two very similar small-molecule ligands of Bcl-xL are considered that cause both severe line broadening of interface residues. We show that one compound exhibits single-mode binding, and broadening is just due to dissociation kinetics in the intermediate exchange regime, and the line broadening can be overcome by providing excess ligand. In the other case, line broadening is due to dissociation kinetics and exchange between multiple bound conformations, and broadening cannot be overcome by providing excess ligand. The procedures used are very general and can also be applied to characterizing protein-protein and protein-nucleic acid interactions.
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