1F4E

CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COMPLEXED WITH TOSYL-D-PROLINE

1F4E の概要

• エントリーDOI: 10.2210/pdb1f4e/pdb
• 関連するPDBエントリー: 1F4B 1F4C 1F4D 1F4F 1F4G
• 分子名称: THYMIDYLATE SYNTHASE, SULFATE ION, TOSYL-D-PROLINE, ... (5 entities in total)
• 機能のキーワード: crystal structure of e. coli thymidylate synthase complexed with tosyl-d-proline, transferase
• 由来する生物種: Escherichia coli
• 細胞内の位置: Cytoplasm : P0A884
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31758.83

構造登録者

Erlanson, D.A.,Braisted, A.C.,Raphael, D.R.,Randal, M.,Stroud, R.M.,Gordon, E.,Wells, J.A. (登録日: 2000-06-07, 公開日: 2000-06-22, 最終更新日: 2024-10-30)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (1.9 Å)