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Related Experiment Videos

Substrate-induced conformational changes in human UMP/CMP kinase.

Dario Segura-Peña1, Nikolina Sekulic, Stephan Ort

  • 1University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics, Chicago, Illinois 60607, USA.

The Journal of Biological Chemistry
|May 28, 2004
PubMed
Summary
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Human UMP/CMP kinase, essential for nucleic acid synthesis and prodrug activation, undergoes significant conformational changes. Its substrate-free open structure reveals an induced fit mechanism crucial for enzyme function.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Human UMP/CMP kinase is vital for nucleotide precursor synthesis.
  • It activates important nucleoside analog prodrugs like gemcitabine.
  • The enzyme exhibits large conformational changes between open and closed states during catalysis.

Purpose of the Study:

  • To determine the crystal structure of the substrate-free, open form of human UMP/CMP kinase.
  • To elucidate the conformational changes upon substrate binding by comparing with known closed states.
  • To understand the enzyme's substrate specificity through homology modeling.

Main Methods:

  • X-ray crystallography was used to obtain the structure of the open form.
  • Comparative analysis of human open and Dictyostelium discoideum closed structures.

Related Experiment Videos

  • Homology modeling of the human enzyme in its closed state.

    • Main Results:

    • The crystal structure of the substrate-free, open human UMP/CMP kinase was determined.
    • Substrate binding induces conformational changes, demonstrating an induced fit mechanism.
    • Rigid body movements of domains facilitate the formation of a catalytically active state.

    Conclusions:

    • Human UMP/CMP kinase utilizes an induced fit mechanism for substrate binding.
    • Structural insights rationalize the enzyme's role in nucleotide synthesis and prodrug activation.
    • Understanding these conformational dynamics is key for drug development.