ArticleProceedings of the National Academy of Sciences of the United States of America2011
Reactibodies generated by kinetic selection couple chemical reactivity with favorable protein dynamics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States.International journal of molecular sciences · 2020Pooled it
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- Two-dimensional high-throughput on-cell screening of immunoglobulins against broad antigen repertoires.Communications biology · 2024Article
- Enzymatization of mouse monoclonal antibodies to the corresponding catalytic antibodies.Scientific reports · 2024Article
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- Obtaining Highly Active Catalytic Antibodies Capable of Enzymatically Cleaving Antigens.International journal of molecular sciences · 2022Article
- Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule.RSC chemical biology · 2021Article
- HIF-DependentFrontiers in genetics · 2021Article
- Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Computational Prediction of the Epitopes of HA1 Protein of Influenza Viruses to its Neutralizing Antibodies.Antibodies (Basel, Switzerland) · 2018Article
- Evolution of catalytic centers of antibodies by virtual screening of broad repertoire of mutants using supercomputer.Doklady. Biochemistry and biophysics · 2017Article
- Robotic QM/MM-driven maturation of antibody combining sites.Science advances · 2016Article
- Multiple sclerosis autoantigen myelin basic protein escapes control by ubiquitination during proteasomal degradation.The Journal of biological chemistry · 2014Article
- Biochemical features of a catalytic antibody light chain, 22F6, prepared from human lymphocytes.The Journal of biological chemistry · 2013Article
- Chemical polysialylation of human recombinant butyrylcholinesterase delivers a long-acting bioscavenger for nerve agents in vivo.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Constant domain-regulated antibody catalysis.The Journal of biological chemistry · 2012Article
- Article
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18 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Igs offer a versatile template for combinatorial and rational design approaches to the de novo creation of catalytically active proteins. We have used a covalent capture selection strategy to identify biocatalysts from within a human semisynthetic antibody variable fragment library that uses a nucleophilic mechanism. Specific phosphonylation at a single tyrosine within the variable light-chain framework was confirmed in a recombinant IgG construct. High-resolution crystallographic structures of unmodified and phosphonylated Fabs display a 15-Å-deep two-chamber cavity at the interface of variable light (V(L)) and variable heavy (V(H)) fragments having a nucleophilic tyrosine at the base of the site. The depth and structure of the pocket are atypical of antibodies in general but can be compared qualitatively with the catalytic site of cholinesterases. A structurally disordered heavy chain complementary determining region 3 loop, constituting a wall of the cleft, is stabilized after covalent modification by hydrogen bonding to the phosphonate tropinol moiety. These features and presteady state kinetics analysis indicate that an induced fit mechanism operates in this reaction. Mutations of residues located in this stabilized loop do not interfere with direct contacts to the organophosphate ligand but can interrogate second shell interactions, because the H3 loop has a conformation adjusted for binding. Kinetic and thermodynamic parameters along with computational docking support the active site model, including plasticity and simple catalytic components. Although relatively uncomplicated, this catalytic machinery displays both stereo- and chemical selectivity. The organophosphate pesticide paraoxon is hydrolyzed by covalent catalysis with rate-limiting dephosphorylation. This reactibody is, therefore, a kinetically selected protein template that has enzyme-like catalytic attributes.
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