Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 34, Pages E542-E549Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1104829108
Keywords
allosteric mechanism; peptide design; protein-protein interface inhibitor
Categories
Funding
- European Union [LSH-2005-2.2.0-8]
- Italian Association for Cancer Research [IG 10474]
- Klaus Tschira Foundation
- Alexander von Humboldt Foundation
- Finnish Cultural Foundation
- Academy of Finland
- University of Kuopio
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Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The LR peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.
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