ArticleeLife2024
A parameterized two-domain thermodynamic model explains diverse mutational effects on protein allostery.
Article in eLife, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- The allostery principle supports the symbolic character of signaling circuits: gene regulation provides a form of intelligence to living systems.Theory in biosciences = Theorie in den Biowissenschaften · 2026Article
- Identification and understanding of allostery hotspots in proteins: Integration of deep mutational scanning and multi-faceted computational analyses.Journal of molecular biology · 2025Review
- Directed Evolution in Escherichia coli for Novel Ligand-Binding Regulators: Evolving a Progesterone-Responsive Transcription Factor to Bind Cortisol.Current protocols · 2025Article
- Machine learning in molecular biophysics: Protein allostery, multi-level free energy simulations, and lipid phase transitions.Biophysics reviews · 2025Review
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- Modulation of Allostery with Multiple Mechanisms by Hotspot Mutations in TetR.bioRxiv : the preprint server for biology · 2023Article
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Abstract
New experimental findings continue to challenge our understanding of protein allostery. Recent deep mutational scanning study showed that allosteric hotspots in the tetracycline repressor (TetR) and its homologous transcriptional factors are broadly distributed rather than spanning well-defined structural pathways as often assumed. Moreover, hotspot mutation-induced allostery loss was rescued by distributed additional mutations in a degenerate fashion. Here, we develop a two-domain thermodynamic model for TetR, which readily rationalizes these intriguing observations. The model accurately captures the in vivo activities of various mutants with changes in physically transparent parameters, allowing the data-based quantification of mutational effects using statistical inference. Our analysis reveals the intrinsic connection of intra- and inter-domain properties for allosteric regulation and illustrate epistatic interactions that are consistent with structural features of the protein. The insights gained from this study into the nature of two-domain allostery are expected to have broader implications for other multi-domain allosteric proteins.
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