Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase
Articolo
Data di Pubblicazione:
2011
Citazione:
Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase / D. Cardinale, G. Guaitoli, D. Tondi, R. Luciani, S. Henrich, O.M.H. Salo-Ahen, S. Ferrari, G. Marverti, D. Guerrieri, A. Ligabue, C. Frassineti, C. Pozzi, S. Mangani, D. Fessas, R. Guerrini, G. Ponterini, R.C. Wade, M.P. Costi. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 108:34(2011), pp. 13889-13890. [10.1073/pnas.1104829108]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
allosteric mechanism ; peptide design ; protein–protein interface inhibitor
Elenco autori:
D. Cardinale, G. Guaitoli, D. Tondi, R. Luciani, S. Henrich, O.M.H. Salo Ahen, S. Ferrari, G. Marverti, D. Guerrieri, A. Ligabue, C. Frassineti, C. Pozzi, S. Mangani, D. Fessas, R. Guerrini, G. Ponterini, R.C. Wade, M.P. Costi
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