3N5E

Crystal Structure of human thymidylate synthase bound to a peptide inhibitor

Summary for 3N5E

• Entry DOI: 10.2210/pdb3n5e/pdb
• Related: 3N5G
• Related PRD ID: PRD_000970
• Descriptor: Thymidylate synthase, Synthetic peptide LR, SULFATE ION, ... (5 entities in total)
• Functional Keywords: peptide inhibitor, protein-peptide complex, interface inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P04818 P04818
• Total number of polymer chains: 3
• Total formula weight: 75962.80

Authors

Pozzi, C.,Cardinale, D.,Guaitoli, G.,Tondi, D.,Luciani, R.,Myllykallio, H.,Ferrari, S.,Costi, M.P.,Mangani, S. (deposition date: 2010-05-25, release date: 2011-06-08, Last modification date: 2023-09-06)

Primary citation

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, C.,Mangani, S.,Fessas, D.,Guerrini, R.,Ponterini, G.,Wade, R.C.,Costi, M.P.
Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.
Proc.Natl.Acad.Sci.USA, 108:E542-E549, 2011

PubMed 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.

PubMed: 21795601
DOI: 10.1073/pnas.1104829108

Experimental method

X-RAY DIFFRACTION (2.26 Å)