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1F4F

CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COMPLEXED WITH SP-722

Summary for 1F4F
Entry DOI10.2210/pdb1f4f/pdb
Related1F4B 1F4C 1F4D 1F4E 1F4G
DescriptorTHYMIDYLATE SYNTHASE, SULFATE ION, 4-[[GLUTAMIC ACID]-CARBONYL]-BENZENE-SULFONYL-D-PROLINE, ... (4 entities in total)
Functional Keywordscrystal structure of e. coli thymidylate synthase complexed with sp-722, transferase
Biological sourceEscherichia coli
Cellular locationCytoplasm : P0A884
Total number of polymer chains2
Total formula weight62456.48
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 citationErlanson, 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: 10944209
DOI: 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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