ArticleMedicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents2020
Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.
Article in Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Redesign of energetically frustrated regions rescues function in defective T4 clamp loaders.Molecular biology and evolution · 2026Article
- Amino acid substitutions at rheostat positions in the NaProtein science : a publication of the Protein Society · 2025Article
- DIVERGE v4: A Platform for Large-Scale Analysis of Functional Divergence Across Multi-Gene Families.Molecular biology and evolution · 2025Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- Structural basis for hepatitis B virus restriction by a viral receptor homologue.Nature communications · 2024Article
- Dynamics-based protein network features accurately discriminate neutral and rheostat positions.Biophysical journal · 2024Article
- Rheostatic contributions to protein stability can obscure a position's functional role.Protein science : a publication of the Protein Society · 2024Article
- Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.The Journal of biological chemistry · 2024Review
- The intrinsically disordered transcriptional activation domain of CIITA is functionally tuneable by single substitutions: An exception or a new paradigm?Protein science : a publication of the Protein Society · 2024Article
- The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation.Archives of biochemistry and biophysics · 2023Article
- PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes.Database : the journal of biological databases and curation · 2023Article
- Odd one out? Functional tuning of Zymomonas mobilis pyruvate kinase is narrower than its allosteric, human counterpart.Protein science : a publication of the Protein Society · 2022Article
- Structural Plasticity Is a Feature of Rheostat Positions in the Human NaInternational journal of molecular sciences · 2022Article
- Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.Protein science : a publication of the Protein Society · 2022Article
- Surface residues and nonadditive interactions stabilize a consensus homeodomain protein.Biophysical journal · 2021Article
- Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.Protein science : a publication of the Protein Society · 2021Article
- A clinically relevant polymorphism in the NaThe Journal of biological chemistryArticle
- Substitutions at rheostat position 52 of LacI have long-range effects on the LacI conformational landscape.Biophysical chemistryArticle
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Authors and funding
5 authors.
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Abstract
To achieve the full potential of pharmacogenomics, one must accurately predict the functional out comes that arise from amino acid substitutions in proteins. Classically, researchers have focused on understanding the consequences of individual substitutions. However, literature surveys have shown that most substitutions were created at evolutionarily conserved positions. Awareness of this bias leads to a shift in perspective, from considering the outcomes of individual substitutions to understanding the roles of individual protein positions. Conserved positions tend to act as "toggle" switches, with most substitutions abolishing function. However, nonconserved positions have been found equally capable of affecting protein function. Indeed, many nonconserved positions act like functional dimmer switches ("rheostat" positions): This is revealed when multiple substitutions are made at a single position. Each substitution has a different functional outcome; the set of substitutions spans arange of outcomes. Finally, some nonconserved positions appear neutral, capable of accommodating all amino acid types without modifying function. This manuscript reviews the currently-known properties of rheost at positions, with examples shown for pyruvate kinase, organic anion transporting polypeptide 1B1, the beta-lactamase inhibitory protein, and angiotensin-converting enzyme 2. Outcomes observed for rheostat positions have implications for the rational design of drug analogs and allosteric drugs. Furthermore, this new framework - comprising three types of protein positions - provides a new approach to interpreting disease and population-based databases of amino acid changes. In conclusion, although a full understanding of substitution out comes at rheostat positions poses a challenge, utilization of this new frame of reference will further advance the application of pharmacogenomics.
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