1juj
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Human Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based Antifolate
OverviewOverview
Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate, compounds, developed as inhibitors of thymidylate synthase (TS) in a, strategy to circumvent drug-resistance, have been determined in complexes, with their in vivo target, human thymidylate synthase, and with the, structurally best-characterized Escherichia coli enzyme, to resolutions of, 2.2-3.0 A. The 2.9 A crystal structure of a complex of human TS with one, of the inhibitors, the multi-targeted antifolate LY231514, demonstrates, that this compound induces a "closed" enzyme conformation and leads to, formation of a covalent bond between enzyme and substrate. This structure, is one of the first liganded human TS structures, and its solution was, aided by mutation to facilitate crystallization. Structures of three other, pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia, coli TS confirm the orientation of this class of inhibitors in the active, site. Specific interactions between the polyglutamyl moiety and a, positively charged groove on the enzyme surface explain the marked, increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they, are polyglutamylated, as mediated in vivo by the cellular enzyme folyl, polyglutamate synthetase.
DiseaseDisease
Known disease associated with this structure: Timothy syndrome OMIM:[114205]
About this StructureAbout this Structure
1JUJ is a Single protein structure of sequence from Homo sapiens with UMP and LYA as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
ReferenceReference
Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases., Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM, J Mol Biol. 2001 Nov 2;313(4):813-29. PMID:11697906
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