Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.95
Classification:TRANSFERASE (METHYLTRANSFERASE)
Release Date:1996-01-29
Deposition Date:1995-08-15
Revision Date:2008-03-03#2011-07-13
Molecular Weight:62860.96
Macromolecule Type:Protein
Residue Count:530
Atom Site Count:4428
DOI:10.2210/pdb1tsd/pdb
Abstract:
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.
Resolution:1.95
Classification:TRANSFERASE (METHYLTRANSFERASE)
Release Date:1996-01-29
Deposition Date:1995-08-15
Revision Date:2008-03-03#2011-07-13
Molecular Weight:62860.96
Macromolecule Type:Protein
Residue Count:530
Atom Site Count:4428
DOI:10.2210/pdb1tsd/pdb
Abstract:
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.
| Date made available | 1996 |
|---|---|
| Publisher | RCSB-PDB |