1F4F
CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COMPLEXED WITH SP-722
Summary for 1F4F
Entry DOI | 10.2210/pdb1f4f/pdb |
Related | 1F4B 1F4C 1F4D 1F4E 1F4G |
Descriptor | THYMIDYLATE SYNTHASE, SULFATE ION, 4-[[GLUTAMIC ACID]-CARBONYL]-BENZENE-SULFONYL-D-PROLINE, ... (4 entities in total) |
Functional Keywords | crystal structure of e. coli thymidylate synthase complexed with sp-722, transferase |
Biological source | Escherichia coli |
Cellular location | Cytoplasm : P0A884 |
Total number of polymer chains | 2 |
Total formula weight | 62456.48 |
Authors | Erlanson, D.A.,Braisted, A.C.,Raphael, D.R.,Randal, M.,Stroud, R.M.,Gordon, E.,Wells, J.A. (deposition date: 2000-06-07, release date: 2000-06-22, Last modification date: 2024-10-30) |
Primary citation | Erlanson, D.A.,Braisted, A.C.,Raphael, D.R.,Randal, M.,Stroud, R.M.,Gordon, E.M.,Wells, J.A. Site-directed ligand discovery. Proc.Natl.Acad.Sci.USA, 97:9367-9372, 2000 Cited by PubMed Abstract: 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. PubMed: 10944209DOI: 10.1073/pnas.97.17.9367 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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