ArticleProceedings of the National Academy of Sciences of the United States of America2023
Intrinsic structural dynamics dictate enzymatic activity and inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 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
11 citing papers in PubMed, 26 citations in OpenAlex.
- Unraveling the Synergistic Inhibition of Human Maltase-Glucoamylase by Baicalein and Acarbose: Integrated Pharmacodynamics and Computational Insights.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Fair and Square: Design, Synthesis and Biological Evaluations of Squaric Acid Derivatives as Novel HDAC8 Inhibitors.ChemMedChem · 2026Article
- Mutational scan of self-cleavage by HIV-1 protease provides new views of a conformationally dynamic mechanism.Journal of virology · 2026Article
- Mutational scan of self-cleavage by HIV-1 protease provides new views of a conformationally dynamic mechanism.bioRxiv : the preprint server for biology · 2025Article
- Activation dynamics of ubiquitin-specific protease 7.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Multimeric protein interaction and complex prediction: Structure, dynamics and function.Computational and structural biotechnology journal · 2025Review
- A combined NMR and deep neural network approach for enhancing the spectral resolution of aromatic side chains in proteins.Science advances · 2024Article
- Enzyme activation by urea reveals the interplay between conformational dynamics and substrate binding: a single-molecule FRET study.bioRxiv : the preprint server for biology · 2024Article
- Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses.Communications biology · 2024Article
- Solution-state methyl NMR spectroscopy of large non-deuterated proteins enabled by deep neural networks.Nature communications · 2024Article
- Intrinsic structural dynamics dictate enzymatic activity and inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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 at 1 institution in 1 country.
Funding
Abstract
Enzymes are known to sample various conformations, many of which are critical for their biological function. However, structural characterizations of enzymes predominantly focus on the most populated conformation. As a result, single-point mutations often produce structures that are similar or essentially identical to those of the wild-type enzyme despite large changes in enzymatic activity. Here, we show for mutants of a histone deacetylase enzyme (HDAC8) that reduced enzymatic activities, reduced inhibitor affinities, and reduced residence times are all captured by the rate constants between intrinsically sampled conformations that, in turn, can be obtained independently by solution NMR spectroscopy. Thus, for the HDAC8 enzyme, the dynamic sampling of conformations dictates both enzymatic activity and inhibitor potency. Our analysis also dissects the functional role of the conformations sampled, where specific conformations distinct from those in available structures are responsible for substrate and inhibitor binding, catalysis, and product dissociation. Precise structures alone often do not adequately explain the effect of missense mutations on enzymatic activity and drug potency. Our findings not only assign functional roles to several conformational states of HDAC8 but they also underscore the paramount role of dynamics, which will have general implications for characterizing missense mutations and designing inhibitors.
Indexed as
Identifiers
What Socratic 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 Socratic graph.