ArticleJournal of the American Chemical Society2015
Cofactor-Mediated Conformational Dynamics Promote Product Release From Escherichia coli Dihydrofolate Reductase via an Allosteric Pathway.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 48 citations in OpenAlex.
- Dynamic claw of dengue protease unveils druggability potential with high affinity allosteric inhibitors.PNAS nexus · 2025Article
- Perturbative diffraction methods resolve a conformational switch that facilitates a two-step enzymatic mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Engineering the Active Site Lid Dynamics to Improve the Catalytic Efficiency of Yeast Cytosine Deaminase.International journal of molecular sciences · 2023Article
- Production of phenylpyruvic acid by engineered L-amino acid deaminase from Proteus mirabilis.Biotechnology letters · 2022Review
- Single-Molecule Sampling of Dihydrofolate Reductase Shows Kinetic Pauses and an Endosteric Effect Linked to Catalysis.ACS catalysis · 2022Article
- Role of Active Site Loop Dynamics in Mediating Ligand Release fromBiochemistry · 2021Article
- Dynamic Preference for NADP/H Cofactor Binding/Release inMolecules (Basel, Switzerland) · 2021Article
- Distal Regions Regulate Dihydrofolate Reductase-Ligand Interactions.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Site-Specific Tryptophan Labels Reveal Local Microsecond-Millisecond Motions of Dihydrofolate Reductase.Molecules (Basel, Switzerland) · 2020Article
- Directional conformer exchange in dihydrofolate reductase revealed by single-molecule nanopore recordings.Nature chemistry · 2020Article
- Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: insights from accelerated molecular dynamics simulations.Nucleic acids research · 2019Article
- Review
- High-pressure protein crystal structure analysis of Escherichia coli dihydrofolate reductase complexed with folate and NADPActa crystallographica. Section D, Structural biology · 2018Article
- Expanding the Paradigm: Intrinsically Disordered Proteins and Allosteric Regulation.Journal of molecular biology · 2018Review
- Measuring the signs of the methylJournal of biomolecular NMR · 2018Article
- Slow Dynamics of Tryptophan-Water Networks in Proteins.Journal of the American Chemical Society · 2018Article
- The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release.Communications biology · 2018Article
- Measurement of protein backboneJournal of biomolecular NMR · 2017Article
- Defining the Structural Basis for Allosteric Product Release from E. coli Dihydrofolate Reductase Using NMR Relaxation Dispersion.Journal of the American Chemical Society · 2017Article
- Mispacking and the Fitness Landscape of the Green Fluorescent Protein Chromophore Milieu.Biochemistry · 2017Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The enzyme dihydrofolate reductase (DHFR, E) from Escherichia coli is a paradigm for the role of protein dynamics in enzyme catalysis. Previous studies have shown that the enzyme progresses through the kinetic cycle by modulating the dynamic conformational landscape in the presence of substrate dihydrofolate (DHF), product tetrahydrofolate (THF), and cofactor (NADPH or NADP(+)). This study focuses on the quantitative description of the relationship between protein fluctuations and product release, the rate-limiting step of DHFR catalysis. NMR relaxation dispersion measurements of millisecond time scale motions for the E:THF:NADP(+) and E:THF:NADPH complexes of wild-type and the Leu28Phe (L28F) point mutant reveal conformational exchange between an occluded ground state and a low population of a closed state. The backbone structures of the occluded ground states of the wild-type and mutant proteins are very similar, but the rates of exchange with the closed excited states are very different. Integrated analysis of relaxation dispersion data and THF dissociation rates measured by stopped-flow spectroscopy shows that product release can occur by two pathways. The intrinsic pathway consists of spontaneous product dissociation and occurs for all THF-bound complexes of DHFR. The allosteric pathway features cofactor-assisted product release from the closed excited state and is utilized only in the E:THF:NADPH complexes. The L28F mutation alters the partitioning between the pathways and results in increased flux through the intrinsic pathway relative to the wild-type enzyme. This repartitioning could represent a general mechanism to explain changes in product release rates in other E. coli DHFR mutants.
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