TY - JOUR
T1 - Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancer drug 1843u89
AU - Weichsel, Andrzej
AU - Montfort, William R.
PY - 1995/12
Y1 - 1995/12
N2 - The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 Â crystal structure of Escherichia coli TS bound to the drug and dUMP reveals that the 1843U89 binding surface includes a hydrophobic patch that is normally buried. To reach this patch, 1843U89 inserts into the wall of theTS active site, resulting in a severe local distortion of the protein. In this new conformation, active-site groups that normally bind to the catalytic cofactor methylene-tetrahydrofolate instead bind to 1843U89 in new ways. This structure provides a rare example of a protein that can bind tightly to distinct substances using a single, flexible, binding surface. This has implications for drug design, as 1843U89 could not have been obtained from current structure-based approaches.
AB - The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 Â crystal structure of Escherichia coli TS bound to the drug and dUMP reveals that the 1843U89 binding surface includes a hydrophobic patch that is normally buried. To reach this patch, 1843U89 inserts into the wall of theTS active site, resulting in a severe local distortion of the protein. In this new conformation, active-site groups that normally bind to the catalytic cofactor methylene-tetrahydrofolate instead bind to 1843U89 in new ways. This structure provides a rare example of a protein that can bind tightly to distinct substances using a single, flexible, binding surface. This has implications for drug design, as 1843U89 could not have been obtained from current structure-based approaches.
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U2 - 10.1038/nsb1295-1095
DO - 10.1038/nsb1295-1095
M3 - Article
C2 - 8846221
AN - SCOPUS:0028785287
VL - 2
SP - 1095
EP - 1101
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1545-9993
IS - 12
ER -