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Enzymes with lid-gated active sites must operate by an induced fit mechanism instead of conformational selection - PubMed

  • ️Tue Jan 01 2008

Enzymes with lid-gated active sites must operate by an induced fit mechanism instead of conformational selection

Sarah M Sullivan et al. Proc Natl Acad Sci U S A. 2008.

Abstract

The induced fit and conformational selection/population shift models are two extreme cases of a continuum aimed at understanding the mechanism by which the final key-lock or active enzyme conformation is achieved upon formation of the correctly ligated enzyme. Structures of complexes representing the Michaelis and enolate intermediate complexes of the reaction catalyzed by phosphoenolpyruvate carboxykinase provide direct structural evidence for the encounter complex that is intrinsic to the induced fit model and not required by the conformational selection model. In addition, 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. The structural data are consistent with a model in that the energy input from substrate association results in changes in the free energy landscape for the protein, allowing for structural transitions along an induced fit pathway.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.

Thermodynamic cycle for the formation of the active key-lock state. The induced fit pathway is represented by the equilibrium constants K1 and K2 whereas the conformational selection pathway is represented by the equilibrium constants K3 and K4.

Fig. 2.
Fig. 2.

The active site of the PEPCK–Mn2+–PGA–Mn2+GDP complex in the (A) closed-lid and (B) open-lid/disordered states. Catalytic residues discussed in the text are rendered as ball-and-stick models whereas the PGA and GDP ligands are rendered as thick sticks. Potential hydrogen bonds and ionic interactions between the ligands and the active site residues are indicated with dashed lines. The protein backbone is rendered as a gray ribbon except for the region corresponding to the active site lid domain (463–474) that is colored yellow. The active site and nucleotide-associated metals are rendered as pink spheres at 0.8 of their van der Waals radius. 2Fo − Fc density rendered at 2σ is shown for PGA and GTP as a blue mesh. The P-loop motif containing S286 and K290 is also labeled. A thick blue arrow indicates the potential phosphoryl transfer distance between the two ligands. This distance is 3.2 and 5.9 Å in A and B, respectively.

Fig. 3.
Fig. 3.

The active site of the PEPCK–Mn2+–β-SP–Mn2+GTP complex in the (A) closed-lid and (B) open-lid/disordered states. The coloring, rendering, and labeling of the figure is identical to that described for Fig. 2. The potential phosphoryl transfer distances between the two ligands are 3.2 and 3.7 Å in A and B, respectively.

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References

    1. Koshland DE. Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci USA. 1958;44:98–104. - PMC - PubMed
    1. Fisher E. The influence of configuration on enzyme activity. (Translated from German) Dtsch Chem Ges. 1894;27:2984–2993.
    1. Antoniou D, Basner J, Nunez S, Schwartz SD. Computational and theoretical methods to explore the relation between enzyme dynamics and catalysis. Chem Rev. 2006;106:3170–3187. - PubMed
    1. Boehr DD, Dyson HJ, Wright PE. An NMR perspective on enzyme dynamics. Chem Rev. 2006;106:3055–3079. - PubMed
    1. Hammes-Schiffer S, Benkovic SJ. Relating protein motion to catalysis. Annu Rev Biochem. 2006;75:519–541. - PubMed

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