ArticleJournal of the American Chemical Society2017
Defining the Structural Basis for Allosteric Product Release from E. coli Dihydrofolate Reductase Using NMR Relaxation Dispersion.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 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
16 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- DHFR Mutants Modulate Their Synchronized Dynamics with the Substrate by Shifting Hydrogen Bond Occupancies.Journal of chemical information and modeling · 2022Article
- Conserved conformational dynamics determine enzyme activity.Science advances · 2022Article
- Single-Molecule Sampling of Dihydrofolate Reductase Shows Kinetic Pauses and an Endosteric Effect Linked to Catalysis.ACS catalysis · 2022Article
- Article
- Role of Active Site Loop Dynamics in Mediating Ligand Release fromBiochemistry · 2021Article
- Two β-Lactamase Variants with Reduced Clavulanic Acid Inhibition Display Different Millisecond Dynamics.Antimicrobial agents and chemotherapy · 2021Article
- Article
- Directional conformer exchange in dihydrofolate reductase revealed by single-molecule nanopore recordings.Nature chemistry · 2020Article
- Protein Dynamics revealed by NMR Relaxation Methods.Emerging topics in life sciences · 2020Article
- A Dynamic Switch in Inactive p38γ Leads to an Excited State on the Pathway to an Active Kinase.Biochemistry · 2019Article
- Branch site bulge conformations in domain 6 determine functional sugar puckers in group II intron splicing.Nucleic acids research · 2019Article
- Chemical Exchange.Methods in enzymology · 2019Article
- High-pressure protein crystal structure analysis of Escherichia coli dihydrofolate reductase complexed with folate and NADPActa crystallographica. Section D, Structural biology · 2018Article
- The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release.Communications biology · 2018Article
- Chemical shift-based methods in NMR structure determination.Progress in nuclear magnetic resonance spectroscopyReview
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The rate-determining step in the catalytic cycle of E. coli dihydrofolate reductase is tetrahydrofolate (THF) product release, which can occur via an allosteric or an intrinsic pathway. The allosteric pathway, which becomes accessible when the reduced cofactor NADPH is bound, involves transient sampling of a higher energy conformational state, greatly increasing the product dissociation rate as compared to the intrinsic pathway that obtains when NADPH is absent. Although the kinetics of this process are known, the enzyme structure and the THF product conformation in the transiently formed excited state remain elusive. Here, we use side-chain proton NMR relaxation dispersion measurements, X-ray crystallography, and structure-based chemical shift predictions to explore the structural basis of allosteric product release. In the excited state of the E:THF:NADPH product release complex, the reduced nicotinamide ring of the cofactor transiently enters the active site where it displaces the pterin ring of the THF product. The p-aminobenzoyl-l-glutamate tail of THF remains weakly bound in a widened binding cleft. Thus, through transient entry of the nicotinamide ring into the active site, the NADPH cofactor remodels the enzyme structure and the conformation of the THF to form a weakly populated excited state that is poised for rapid product release.
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.