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.

Crystal Structure of human thymidylate synthase bound to a peptide inhibitor / Pozzi, Cristina; Cardinale, Daniela; Guaitoli, G.; Tondi, Donatella; Luciani, Rosaria; Myllykallio, H.; Ferrari, Stefania; Costi, Maria Paola; Mangani, S.. - ELETTRONICO. - (2011), pp. 1-1. [10.2210/pdb3n5e/pdb]

Crystal Structure of human thymidylate synthase bound to a peptide inhibitor

POZZI, Cristina;CARDINALE, Daniela;TONDI, Donatella;LUCIANI, Rosaria;FERRARI, Stefania;COSTI, Maria Paola;
2011

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.
2011
Pozzi, Cristina; Cardinale, Daniela; Guaitoli, G.; Tondi, Donatella; Luciani, Rosaria; Myllykallio, H.; Ferrari, Stefania; Costi, Maria Paola; Mangani...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1063009
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