ArticleHuman mutation2017
Exploring the limits of the usefulness of mutagenesis in studies of allosteric mechanisms.
Article in Human mutation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- BioMutation: a portable graphical user interface for mutagenesis and feature analysis in proteins, nucleic acids, and their complexes.Frontiers in genetics · 2026Article
- Bio-Chemoinformatics-Driven Analysis of nsp7 and nsp8 Mutations and Their Effects on Viral Replication Protein Complex Stability.Current issues in molecular biology · 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
- CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods.Genome biology · 2024Article
- 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
- 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
- Article
- AlloSigMA 2: paving the way to designing allosteric effectors and to exploring allosteric effects of mutations.Nucleic acids research · 2020Article
- Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2020Article
- Functional tunability from a distance: Rheostat positions influence allosteric coupling between two distant binding sites.Scientific reports · 2019Article
- Mutational mimics of allosteric effectors: a genome editing design to validate allosteric drug targets.Scientific reports · 2019Article
- RheoScale: A tool to aggregate and quantify experimentally determined substitution outcomes for multiple variants at individual protein positions.Human mutation · 2018Article
- Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response.PLoS computational biology · 2018Article
- Reports from CAGI: The Critical Assessment of Genome Interpretation.Human mutation · 2017Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
The outcome of structure-guided mutational analyses is often used in support of postulated mechanisms of protein allostery. However, the limits of how informative mutations can be in understanding allosteric mechanisms are not completely clear. Here, we report an exercise to evaluate whether mutational data can support a simplistic mechanistic model, developed with minimal data inputs. Due to the lack of a mechanism to explain how alanine allosterically modifies the affinity of human liver pyruvate kinase (approved symbol PKLR) for its substrate, phosphoenolpyruvate, we proposed a speculative allosteric mechanism for this system. Within the allosteric amino-acid-binding site (something in the effector site must, of necessity, contribute to the allosteric mechanism), we implemented multiple mutational strategies: (1) site-directed random mutagenesis at positions that contact bound alanine and (2) mutations to probe specific questions. Despite acknowledged inadequacies used to formulate the speculative mechanism, many mutations modified the allosteric coupling constant (Q
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