ArticleProceedings of the National Academy of Sciences of the United States of America2012
Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Neutrophil Secretory Proteins Inhibit Calcium Oxalate Crystallisation and Crystal Growth, but Promote Crystal Aggregation.Immunology · 2026Article
- Reprogramming of bacterial virulence by lysine acetylation.Nature communications · 2026Article
- Structural basis of GAIN domain autoproteolysis and cleavage-resistance in the adhesion G-protein coupled receptors.Nature communications · 2026Article
- Conformational preorganization of neighbouring groups modulates and expedites polymer self-deconstruction.Nature chemistry · 2026Article
- Structural and biophysical studies of new L-asparaginase variants: lessons from random mutagenesis of the prototypic Escherichia coli Ntn-amidohydrolase.Acta crystallographica. Section D, Structural biology · 2022Article
- Review
- Molecular mechanism of activation of the immunoregulatory amidase NAAA.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The structure of the PanD/PanZ protein complex reveals negative feedback regulation of pantothenate biosynthesis by coenzyme A.Chemistry & biology · 2015Article
- Why Ser and not Thr brokers catalysis in the trypsin fold.Biochemistry · 2015Article
- An ancient autoproteolytic domain found in GAIN, ZU5 and Nucleoporin98.Journal of molecular biology · 2014Article
- Exploring the role of conformational heterogeneity in cis-autoproteolytic activation of ThnT.Biochemistry · 2014Article
- The CD27L and CTP1L endolysins targeting Clostridia contain a built-in trigger and release factor.PLoS pathogens · 2014Article
- MEROPS: the database of proteolytic enzymes, their substrates and inhibitors.Nucleic acids research · 2014Article
- Intrinsic evolutionary constraints on protease structure, enzyme acylation, and the identity of the catalytic triad.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Uncoupling intramolecular processing and substrate hydrolysis in the N-terminal nucleophile hydrolase hASRGL1 by circular permutation.ACS chemical biology · 2012Article
- Autoproteolytic activation of ThnT results in structural reorganization necessary for substrate binding and catalysis.Journal of molecular biology · 2012Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
ThnT is a pantetheine hydrolase from the DmpA/OAT superfamily involved in the biosynthesis of the β-lactam antibiotic thienamycin. We performed a structural and mechanistic investigation into the cis-autoproteolytic activation of ThnT, a process that has not previously been subject to analysis within this superfamily of enzymes. Removal of the γ-methyl of the threonine nucleophile resulted in a rate deceleration that we attribute to a reduction in the population of the reactive rotamer. This phenomenon is broadly applicable and constitutes a rationale for the evolutionary selection of threonine nucleophiles in autoproteolytic systems. Conservative substitution of the nucleophile (T282C) allowed determination of a 1.6-Å proenzyme ThnT crystal structure, which revealed a level of structural flexibility not previously observed within an autoprocessing active site. We assigned the major conformer as a nonreactive state that is unable to populate a reactive rotamer. Our analysis shows the system is activated by a structural rearrangement that places the scissile amide into an oxyanion hole and forces the nucleophilic residue into a forbidden region of Ramachandran space. We propose that conformational strain may drive autoprocessing through the destabilization of nonproductive states. Comparison of our data with previous reports uncovered evidence that many inactivated structures display nonreactive conformations. For penicillin and cephalosporin acylases, this discrepancy between structure and function may be resolved by invoking the presence of a hidden conformational state, similar to that reported here for ThnT.
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