ArticleMolecular biology and evolution2015
Quantitative Description of a Protein Fitness Landscape Based on Molecular Features.
Article in Molecular biology and evolution, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 71 citations in OpenAlex.
- Review
- Predatory myxobacteria lay at the cross-roads of metallo-β-lactamase evolution.Communications biology · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- Exploiting the fitness cost of metallo-β-lactamase expression can overcome antibiotic resistance in bacterial pathogens.Nature microbiology · 2025Article
- Robust genome and cell engineering via in vitro and in situ circularized RNAs.Nature biomedical engineering · 2025Article
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- Sampling Strategies for Experimentally Mapping Molecular Fitness Landscapes Using High-Throughput Methods.Journal of molecular evolution · 2024Article
- Article
- Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase.Nature catalysis · 2024Article
- In-cell kinetic stability is an essential trait in metallo-β-lactamase evolution.Nature chemical biology · 2023Article
- Metallo-Beta-Lactamase-like Encoding Genes in Candidate Phyla Radiation: Widespread and Highly Divergent Proteins with Potential Multifunctionality.Microorganisms · 2023Article
- Genotype-phenotype landscapes for immune-pathogen coevolution.Trends in immunology · 2023Review
- A multi-layered computational structural genomics approach enhances domain-specific interpretation of Kleefstra syndrome variants in EHMT1.Computational and structural biotechnology journal · 2023Article
- Experimental andACS infectious diseases · 2022Article
- Article
- Metallo-β-lactamases and a tug-of-war for the available zinc at the host-pathogen interface.Current opinion in chemical biology · 2022Review
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- The adaptive landscape of a metallo-enzyme is shaped by environment-dependent epistasis.Nature communications · 2021Article
- Molecular Evolution of Transition Metal Bioavailability at the Host-Pathogen Interface.Trends in microbiology · 2021Review
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Understanding the driving forces behind protein evolution requires the ability to correlate the molecular impact of mutations with organismal fitness. To address this issue, we employ here metallo-β-lactamases as a model system, which are Zn(II) dependent enzymes that mediate antibiotic resistance. We present a study of all the possible evolutionary pathways leading to a metallo-β-lactamase variant optimized by directed evolution. By studying the activity, stability and Zn(II) binding capabilities of all mutants in the preferred evolutionary pathways, we show that this local fitness landscape is strongly conditioned by epistatic interactions arising from the pleiotropic effect of mutations in the different molecular features of the enzyme. Activity and stability assays in purified enzymes do not provide explanatory power. Instead, measurement of these molecular features in an environment resembling the native one provides an accurate description of the observed antibiotic resistance profile. We report that optimization of Zn(II) binding abilities of metallo-β-lactamases during evolution is more critical than stabilization of the protein to enhance fitness. A global analysis of these parameters allows us to connect genotype with fitness based on quantitative biochemical and biophysical parameters.
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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 OpenQuestion graph.