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PDBsum entry 3n5e
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Transferase/transferase inhibitor
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PDB id
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3n5e
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References listed in PDB file
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Key reference
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Title
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Protein-Protein interface-Binding peptides inhibit the cancer therapy target human thymidylate synthase.
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Authors
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D.Cardinale,
G.Guaitoli,
D.Tondi,
R.Luciani,
S.Henrich,
O.M.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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Ref.
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Proc Natl Acad Sci U S A, 2011,
108,
E542.
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PubMed id
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Abstract
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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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