ArticleThe Journal of biological chemistry2014
Protein dynamics control the progression and efficiency of the catalytic reaction cycle of the Escherichia coli DNA-repair enzyme AlkB.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- Article
- Cancer-associated TRF1 mutations alter PARP1 interaction dynamics: an in silico study.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Structure-based Discovery of a Non-competitive FTO Inhibitor Bound to a Cryptic Site at the Domain Interface.Journal of molecular biology · 2026Article
- Article
- Unravelling 2-oxoglutarate turnover and substrate oxidation dynamics in 5-methylcytosine-oxidising TET enzymes.Communications chemistry · 2024Article
- An α-ketoglutarate conformational switch controls iron accessibility, activation, and substrate selection of the human FTO protein.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The Role of Key Amino Acids of the Human Fe(II)/2OG-Dependent Dioxygenase ALKBH3 in Structural Dynamics and Repair Activity toward Methylated DNA.International journal of molecular sciences · 2024Article
- Article
- Conformational Dynamics of Human ALKBH2 Dioxygenase in the Course of DNA Repair as Revealed by Stopped-Flow Fluorescence Spectroscopy.Molecules (Basel, Switzerland) · 2022Article
- Spectroscopic and in vitro Investigations of FeChembiochem : a European journal of chemical biology · 2022Review
- Solution structure ensemble of human obesity-associated protein FTO reveals druggable surface pockets at the interface between the N- and C-terminal domain.The Journal of biological chemistry · 2022Article
- Article
- Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family.Cellular and molecular life sciences : CMLS · 2021Review
- Role of Structural Dynamics in Selectivity and Mechanism of Non-heme Fe(II) and 2-Oxoglutarate-Dependent Oxygenases Involved in DNA Repair.ACS central science · 2020Article
- Transient kinetic analysis of oxidative dealkylation by the direct reversal DNA repair enzyme AlkB.The Journal of biological chemistry · 2020Article
- A Single-Turnover Kinetic Study of DNA Demethylation Catalyzed by Fe(II)/α-Ketoglutarate-Dependent Dioxygenase AlkB.Molecules (Basel, Switzerland) · 2019Article
- Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern.Nature communications · 2019Article
- Protein Flexibility of the α-Ketoglutarate-Dependent Oxygenase Factor-Inhibiting HIF-1: Implications for Substrate Binding, Catalysis, and Regulation.Biochemistry · 2019Article
- Detection of chemical exchange in methyl groups of macromolecules.Journal of biomolecular NMR · 2019Article
- Active Site Breathing of Human Alkbh5 Revealed by Solution NMR and Accelerated Molecular Dynamics.Biophysical journal · 2018Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
A central goal of enzymology is to understand the physicochemical mechanisms that enable proteins to catalyze complex chemical reactions with high efficiency. Recent methodological advances enable the contribution of protein dynamics to enzyme efficiency to be explored more deeply. Here, we utilize enzymological and biophysical studies, including NMR measurements of conformational dynamics, to develop a quantitative mechanistic scheme for the DNA repair enzyme AlkB. Like other iron/2-oxoglutarate-dependent dioxygenases, AlkB employs a two-step mechanism in which oxidation of 2-oxoglutarate generates a highly reactive enzyme-bound oxyferryl intermediate that, in the case of AlkB, slowly hydroxylates an alkylated nucleobase. Our results demonstrate that a microsecond-to-millisecond time scale conformational transition facilitates the proper sequential order of substrate binding to AlkB. Mutations altering the dynamics of this transition allow generation of the oxyferryl intermediate but promote its premature quenching by solvent, which uncouples 2-oxoglutarate turnover from nucleobase oxidation. Therefore, efficient catalysis by AlkB depends upon the dynamics of a specific conformational transition, establishing another paradigm for the control of enzyme function by protein dynamics.
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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.