1SYN

E. COLI THYMIDYLATE SYNTHASE IN COMPLEX WITH BW1843U89 AND 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP)

Summary for 1SYN

• Entry DOI: 10.2210/pdb1syn/pdb
• Descriptor: THYMIDYLATE SYNTHASE, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC ACID, ... (4 entities in total)
• Functional Keywords: transferase (methyltransferase)
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P0A884
• Total number of polymer chains: 2
• Total formula weight: 62704.69

Authors

Stout, T.J.,Stroud, R.M. (deposition date: 1995-09-19, release date: 1996-01-29, Last modification date: 2024-06-05)

Primary citation

Stout, T.J.,Stroud, R.M.
The complex of the anti-cancer therapeutic, BW1843U89, with thymidylate synthase at 2.0 A resolution: implications for a new mode of inhibition.
Structure, 4:67-77, 1996

PubMed Abstract: Thymidylate synthase (TS) is critical to DNA synthesis as it catalyzes the rate limiting step in the only biosynthetic pathway for deoxythymidine monophosphate (dTMP) production. TS is therefore an important target for anti-proliferative and anti-cancer drug design. The TS enzymatic mechanism involves the reductive methylation of the substrate, deoxyuridine monophosphate (dUMP), by transfer of a methylene group from the co-factor, methylenetetrahydrofolate (CH2H4folate), resulting in the production of deoxythymidine monophosphate (dTMP) and dihydrofolate (H2folate). Previous drug design efforts based on co-factor analogues have produced good inhibitors of TS, but poor bioavailability and toxicity have limited their usefulness. BW1843U89, a folate analogue, is a recently developed compound which is an exceptionally strong inhibitor (Ki = 0.09 nM), has good bioavailability and in clinical trials thus far has not demonstrated significant toxicity.

PubMed: 8805515
DOI: 10.1016/S0969-2126(96)00010-X

Experimental method

X-RAY DIFFRACTION (2 Å)