1f4f
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CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COMPLEXED WITH SP-722
OverviewOverview
We report a strategy (called "tethering") to discover low molecular weight, ligands ( approximately 250 Da) that bind weakly to targeted sites on, proteins through an intermediary disulfide tether. A native or engineered, cysteine in a protein is allowed to react reversibly with a small library, of disulfide-containing molecules ( approximately 1,200 compounds) at, concentrations typically used in drug screening (10 to 200 microM). The, cysteine-captured ligands, which are readily identified by MS, are among, the most stable complexes, even though in the absence of the covalent, tether the ligands may bind very weakly. This method was applied to, generate a potent inhibitor for thymidylate synthase, an essential enzyme, in pyrimidine metabolism with therapeutic applications in cancer and, infectious diseases. The affinity of the untethered ligand (K(i), approximately 1 mM) was improved 3,000-fold by synthesis of a small set of, analogs with the aid of crystallographic structures of the tethered, complex. Such site-directed ligand discovery allows one to nucleate drug, design from a spatially targeted lead fragment.
About this StructureAbout this Structure
1F4F is a Single protein structure of sequence from Escherichia coli with SO4 and TP3 as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
ReferenceReference
Site-directed ligand discovery., Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA, Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9367-72. PMID:10944209
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