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==Overview== | ==Overview== | ||
Two crystal structures of rat thymidylate synthase (TS) complexed with, dUMP and the anticancer drug Tomudex (ZD1694) have been determined to, resolutions of 3.3 and 2.6 A. Tomudex is one of several new antifolates, targeted to TS and the first to be approved for clinical use. The, structures represent the first views of any mammalian TS bound to ligands, and suggest that the rat protein undergoes a ligand-induced conformational, change similar to that of the Escherichia coli protein. Surprisingly, Tomudex does not induce the "closed" conformation in rat TS that is seen, on binding to E. coli TS, resulting in inhibitor atoms that differ in, position by more than 1.5 A. Several species-specific differences in, sequence may be the reason for this. Phe 74 shifts to a new position in, the rat ... | Two crystal structures of rat thymidylate synthase (TS) complexed with, dUMP and the anticancer drug Tomudex (ZD1694) have been determined to, resolutions of 3.3 and 2.6 A. Tomudex is one of several new antifolates, targeted to TS and the first to be approved for clinical use. The, structures represent the first views of any mammalian TS bound to ligands, and suggest that the rat protein undergoes a ligand-induced conformational, change similar to that of the Escherichia coli protein. Surprisingly, Tomudex does not induce the "closed" conformation in rat TS that is seen, on binding to E. coli TS, resulting in inhibitor atoms that differ in, position by more than 1.5 A. Several species-specific differences in, sequence may be the reason for this. Phe 74 shifts to a new position in, the rat complex and is in van der Waals contact with the inhibitor, while, in the E. coli protein the equivalent amino acid (His 51) hydrogen bonds, to the glutamate portion of the inhibitor. Amino acids Arg 101, Asn 106, and Met 305 make no contacts with the inhibitor in the open conformation, unlike the equivalent residues in the E. coli protein (Thr 78, Trp 83, and, Val 262). dUMP binding is similar in both proteins, except that there is, no covalent adduct to the active site cysteine (Cys 189) in the rat, structures. Two insertions in the rat protein are clearly seen, but the, N-termini (residues 1-20) and C-termini (residues 301-307) are disordered, in both crystal forms. | ||
==About this Structure== | ==About this Structure== | ||
2TSR is a | 2TSR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with UMP and D16 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] Structure known Active Site: NUL. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2TSR OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: tomudex]] | [[Category: tomudex]] | ||
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Revision as of 14:25, 5 November 2007
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THYMIDYLATE SYNTHASE FROM RAT IN TERNARY COMPLEX WITH DUMP AND TOMUDEX
OverviewOverview
Two crystal structures of rat thymidylate synthase (TS) complexed with, dUMP and the anticancer drug Tomudex (ZD1694) have been determined to, resolutions of 3.3 and 2.6 A. Tomudex is one of several new antifolates, targeted to TS and the first to be approved for clinical use. The, structures represent the first views of any mammalian TS bound to ligands, and suggest that the rat protein undergoes a ligand-induced conformational, change similar to that of the Escherichia coli protein. Surprisingly, Tomudex does not induce the "closed" conformation in rat TS that is seen, on binding to E. coli TS, resulting in inhibitor atoms that differ in, position by more than 1.5 A. Several species-specific differences in, sequence may be the reason for this. Phe 74 shifts to a new position in, the rat complex and is in van der Waals contact with the inhibitor, while, in the E. coli protein the equivalent amino acid (His 51) hydrogen bonds, to the glutamate portion of the inhibitor. Amino acids Arg 101, Asn 106, and Met 305 make no contacts with the inhibitor in the open conformation, unlike the equivalent residues in the E. coli protein (Thr 78, Trp 83, and, Val 262). dUMP binding is similar in both proteins, except that there is, no covalent adduct to the active site cysteine (Cys 189) in the rat, structures. Two insertions in the rat protein are clearly seen, but the, N-termini (residues 1-20) and C-termini (residues 301-307) are disordered, in both crystal forms.
About this StructureAbout this Structure
2TSR is a Single protein structure of sequence from Rattus norvegicus with UMP and D16 as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Structure known Active Site: NUL. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug., Sotelo-Mundo RR, Ciesla J, Dzik JM, Rode W, Maley F, Maley GF, Hardy LW, Montfort WR, Biochemistry. 1999 Jan 19;38(3):1087-94. PMID:9894005
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