1f4c

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{{STRUCTURE_1f4c| PDB=1f4c | SCENE= }}
{{STRUCTURE_1f4c| PDB=1f4c | SCENE= }}
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'''CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COVALENTLY MODIFIED AT C146 WITH N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL'''
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===CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COVALENTLY MODIFIED AT C146 WITH N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_10944209}}
==About this Structure==
==About this Structure==
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[[Category: Wells, J A.]]
[[Category: Wells, J A.]]
[[Category: E. coli thymidylate synthase modified at cysteine 146]]
[[Category: E. coli thymidylate synthase modified at cysteine 146]]
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Revision as of 23:40, 30 June 2008

Image:1f4c.png

Template:STRUCTURE 1f4c

CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COVALENTLY MODIFIED AT C146 WITH N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL

Template:ABSTRACT PUBMED 10944209

About this Structure

1F4C is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

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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