Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancer drug 1843U89.
The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 A 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 the TS 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.
Weichsel
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Department of Biochemistry, University of Arizona Tucson 85721, USA.
Montfort
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D000970:Antineoplastic Agents / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D003461:Crystallography; D007211:Indoles / Q000378:metabolism*; D054833:Isoindoles; D008024:Ligands; D011487:Protein Conformation; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
D000970:Antineoplastic Agents; D007211:Indoles; D054833:Isoindoles; D008024:Ligands; D011799:Quinazolines; C079601:1843U89; D013940:Thymidylate Synthase