• Corpus ID: 18850205

Conformational selection and induced changes along the catalytic cycle of E. coli DHFR

@article{Weikl2012ConformationalSA,
  title={Conformational selection and induced changes along the catalytic cycle of E. coli DHFR},
  author={Thomas R. Weikl and David D. Boehr},
  journal={arXiv: Biomolecules},
  year={2012}
}
Protein function often involves changes between different conformations. Central questions are how these conformational changes are coupled to the binding or catalytic processes during which they occur, and how they affect the catalytic rates of enzymes. An important model system is the enzyme dihydrofolate reductase (DHFR) from E. coli, which exhibits characteristic conformational changes of the active-site loop during the catalytic step and during unbinding of the product. In this article, we… 

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SHOWING 1-10 OF 74 REFERENCES
Conformational relaxation following hydride transfer plays a limiting role in dihydrofolate reductase catalysis.
TLDR
It is demonstrated that in dihydrofolate reductase the closed to occluded conformational change in the product ternary complex also gates progression through the catalytic cycle, and that the rate of this process places an effective limit on the maximum rate of the hydride transfer step.
Conformational changes in the active site loops of dihydrofolate reductase during the catalytic cycle.
TLDR
The data show that DHFR exists in solution in two dominant conformational states, with the active site loops adopting conformations that closely approximate the occluded or closed conformations identified in earlier X-ray crystallographic analyses.
Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis.
TLDR
Observations of a ternary complex formed from the substrate analog folate and oxidized NADP+ cofactor revealed conformational exchange between a ground state, in which the active site loops adopt a closed conformation, and a weakly populated state with the loops in the occluded conformation.
Structure, dynamics, and catalytic function of dihydrofolate reductase.
TLDR
These studies provide a detailed map of changes in conformation and dynamics throughout the catalytic cycle of DHFR and give new insights into the role of protein motions in the catalysttic activity of this enzyme.
Enzymes with lid-gated active sites must operate by an induced fit mechanism instead of conformational selection
TLDR
The structural data demonstrate that the conformational selection model is not sufficient to explain the correlation between dynamics and catalysis in phosphoenolpyruvate carboxykinase and other enzymes in which the transition between the uninduced and the induced conformations occludes the active site from the solvent.
Effects of a distal mutation on active site chemistry.
TLDR
Findings support theoretical studies suggesting that the G121V mutation led to a different conformational ensemble of reactive states and less effective rearrangement of the potential surface but has an only weak effect on H-tunneling.
Trapping Conformational States Along Ligand-Binding Dynamics of Peptide Deformylase: The Impact of Induced Fit on Enzyme Catalysis
TLDR
This work provides a detailed mechanism for an induced-fit process at atomic resolution of a slow, tight binding inhibitor-enzyme system, actinonin-peptide deformylase, and solves crystal structures of the initial open state and final closed state.
The catalytic effect of dihydrofolate reductase and its mutants is determined by reorganization energies.
TLDR
The effect of distant mutations on the catalytic reaction of dihydrofolate reductase (DHFR) is reexamined by empirical valence bond simulations and shows that the changes in activation barriers are strongly correlated with the corresponding changes in the reorganization energy.
Interloop contacts modulate ligand cycling during catalysis by Escherichia coli dihydrofolate reductase.
TLDR
The findings suggest that the role of the interloop interaction between the betaG-betaH loop and the Met20 loop is to modulate ligand off rates allowing for proper cycling through the preferred kinetic pathway.
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