ArticleStructure (London, England : 1993)2017
Flexibility and Design: Conformational Heterogeneity along the Evolutionary Trajectory of a Redesigned Ubiquitin.
Article in Structure (London, England : 1993), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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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.
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Who cites it
17 citing papers in PubMed, 34 citations in OpenAlex.
- Multistate Enzyme Design Enables Efficient and Stereoselective Multistep Catalysis.bioRxiv : the preprint server for biology · 2026Article
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- Structure-Based Experimental Datasets for Benchmarking Protein Simulation Force Fields [Article v1.0].Living journal of computational molecular science · 2025Article
- Ubiquitin's Conformational Heterogeneity as Discerned by Nuclear Magnetic Resonance Spectroscopy.Chembiochem : a European journal of chemical biology · 2024Review
- Article
- Uncovering Protein Ensembles: Automated Multiconformer Model Building for X-ray Crystallography and Cryo-EM.bioRxiv : the preprint server for biology · 2024Article
- Design of efficient artificial enzymes using crystallographically-enhanced conformational sampling.bioRxiv : the preprint server for biology · 2023Article
- Structural and functional characterization of USP47 reveals a hot spot for inhibitor design.Communications biology · 2023Article
- Ensemble-function relationships to dissect mechanisms of enzyme catalysis.Science advances · 2022Article
- Evaluating the impact of X-ray damage on conformational heterogeneity in room-temperature (277 K) and cryo-cooled protein crystals.Acta crystallographica. Section D, Structural biology · 2022Article
- Ensemble-based enzyme design can recapitulate the effects of laboratory directed evolution in silico.Nature communications · 2020Article
- Advances in methods for atomic resolution macromolecular structure determination.F1000Research · 2020Review
- Temperature-jump solution X-ray scattering reveals distinct motions in a dynamic enzyme.Nature chemistry · 2019Article
- Origin of conformational dynamics in a globular protein.Communications biology · 2019Article
- Directed Evolution Mimics Allosteric Activation by Stepwise Tuning of the Conformational Ensemble.Journal of the American Chemical Society · 2018Article
- Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
Although protein design has been used to introduce new functions, designed variants generally only function as well as natural proteins after rounds of laboratory evolution. One possibility for this pattern is that designed mutants frequently sample nonfunctional conformations. To test this idea, we exploited advances in multiconformer modeling of room-temperature X-ray data collection on redesigned ubiquitin variants selected for increasing binding affinity to the deubiquitinase USP7. Initial core mutations disrupt natural packing and lead to increased flexibility. Additional, experimentally selected mutations quenched conformational heterogeneity through new stabilizing interactions. Stabilizing interactions, such as cation-pi stacking and ordered waters, which are not included in standard protein design energy functions, can create specific interactions that have long-range effects on flexibility across the protein. Our results suggest that increasing flexibility may be a useful strategy to escape local minima during initial directed evolution and protein design steps when creating new functions.
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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 OpenQuestion graph.