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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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PDB id:
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Transferase/transferase inhibitor
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Title:
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Crystal structure of human thymidylate synthase bound to a peptide inhibitor
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Structure:
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Thymidylate synthase. Chain: a. Synonym: tsase, ts. Engineered: yes. Thymidylate synthase. Chain: b. Synonym: tsase, ts. Engineered: yes. Synthetic peptide lr.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: tyms, ts, ok/sw-cl.29. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic peptide (8mer)
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Resolution:
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2.26Å
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R-factor:
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0.189
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R-free:
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0.221
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Authors:
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C.Pozzi,D.Cardinale,G.Guaitoli,D.Tondi,R.Luciani,H.Myllykallio, S.Ferrari,M.P.Costi,S.Mangani
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Key ref:
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D.Cardinale
et al.
(2011).
Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.
Proc Natl Acad Sci U S A,
108,
E542.
PubMed id:
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Date:
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25-May-10
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Release date:
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08-Jun-11
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PROCHECK
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Headers
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References
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P04818
(TYSY_HUMAN) -
Thymidylate synthase from Homo sapiens
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Seq:
Struc:
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313 a.a.
263 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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Enzyme class:
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E.C.2.1.1.45
- thymidylate synthase.
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Pathway:
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Folate Coenzymes
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Reaction:
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dUMP + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate = 7,8-dihydrofolate + dTMP
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dUMP
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+
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(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate
Bound ligand (Het Group name = )
matches with 40.91% similarity
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=
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7,8-dihydrofolate
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+
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dTMP
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Proc Natl Acad Sci U S A
108:E542
(2011)
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PubMed id:
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Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.
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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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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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Links
