ArticleJournal of molecular biology2012
Structural analyses of covalent enzyme-substrate analog complexes reveal strengths and limitations of de novo enzyme design.
Article in Journal of molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed.
- Tools For Building Artificial Biological Nanostructures.ACS nano · 2026Review
- Water will Find Its Way: Transport through Narrow Tunnels in Hydrolases.Journal of chemical information and modeling · 2024Article
- Protein Flexibility and Stiffness Enable Efficient Enzymatic Catalysis.Journal of the American Chemical Society · 2019Article
- Insights from molecular dynamics simulations for computational protein design.Molecular systems design & engineering · 2017Article
- Computational strategies for the design of new enzymatic functions.Archives of biochemistry and biophysics · 2015Review
- Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently.Chemical Society reviews · 2015Review
- Identification of new members of the MAPK gene family in plants shows diverse conserved domains and novel activation loop variants.BMC genomics · 2015Article
- Protein and oligonucleotide delivery systems for vaginal microbicides against viral STIs.Cellular and molecular life sciences : CMLS · 2015Review
- Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- A highly efficient cocaine-detoxifying enzyme obtained by computational design.Nature communications · 2014Article
- Computational design of protein-small molecule interfaces.Journal of structural biology · 2014Article
- Exploration of alternate catalytic mechanisms and optimization strategies for retroaldolase design.Journal of molecular biology · 2014Article
- The effect of the hydrophobic environment on the retro-aldol reaction: comparison to a computationally-designed enzyme.Organic & biomolecular chemistry · 2013Article
- Article
- Evolution of a designed retro-aldolase leads to complete active site remodeling.Nature chemical biology · 2013Article
- Computational protein engineering: bridging the gap between rational design and laboratory evolution.International journal of molecular sciences · 2012Review
- Robust design and optimization of retroaldol enzymes.Protein science : a publication of the Protein Society · 2012Article
- Computational tools for rational protein engineering of aldolases.Computational and structural biotechnology journal · 2012Review
- Recent advances in rational approaches for enzyme engineering.Computational and structural biotechnology journal · 2012Review
- Binding pocket optimization by computational protein design.PloS one · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors.
Funding
Abstract
We report the cocrystal structures of a computationally designed and experimentally optimized retro-aldol enzyme with covalently bound substrate analogs. The structure with a covalently bound mechanism-based inhibitor is similar to, but not identical with, the design model, with an RMSD of 1.4 Å over active-site residues and equivalent substrate atoms. As in the design model, the binding pocket orients the substrate through hydrophobic interactions with the naphthyl moiety such that the oxygen atoms analogous to the carbinolamine and β-hydroxyl oxygens are positioned near a network of bound waters. However, there are differences between the design model and the structure: the orientation of the naphthyl group and the conformation of the catalytic lysine are slightly different; the bound water network appears to be more extensive; and the bound substrate analog exhibits more conformational heterogeneity than typical native enzyme-inhibitor complexes. Alanine scanning of the active-site residues shows that both the catalytic lysine and the residues around the binding pocket for the substrate naphthyl group make critical contributions to catalysis. Mutating the set of water-coordinating residues also significantly reduces catalytic activity. The crystal structure of the enzyme with a smaller substrate analog that lacks naphthyl ring shows the catalytic lysine to be more flexible than in the naphthyl-substrate complex; increased preorganization of the active site would likely improve catalysis. The covalently bound complex structures and mutagenesis data highlight the strengths and weaknesses of the de novo enzyme design strategy.
Indexed as
Identifiers
What OpenQuestion holds
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.