Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5955
Title: Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.
Authors: Cardinale, D
Guaitoli, G
Tondi, D
Luciani, R
Henrich, S
SALO AHEN O., M
Ferrari, S
Marverti, G
Guerrieri, D
Ligabue, A
Frassineti, C
Pozzi, Cecilia 
Mangani, Stefano 
Fessas, D
Guerrini, R
Ponterini, G
WADE R., C
Costi, M. P.
Keywords: allosteric mechanism; peptide design; protein–protein interface inhibitor
Issue Date: 2011
Project: None 
Journal: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Abstract: 
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.
Description: 
21850
URI: http://hdl.handle.net/20.500.12779/5955
ISSN: 0027-8424
DOI: 10.1073/pnas.1104829108
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