1e2j
|
THE NUCLEOSIDE BINDING SITE OF HERPES SIMPLEX TYPE 1 THYMIDINE KINASE ANALYZED BY X-RAY CRYSTALLOGRAPHY
OverviewOverview
The crystal structures of the full-length Herpes simplex virus type 1, thymidine kinase in its unligated form and in a complex with an adenine, analogue have been determined at 1.9 A resolution. The unligated enzyme, contains four water molecules in the thymidine pocket and reveals a small, induced fit on substrate binding. The structure of the ligated enzyme, shows for the first time a bound adenine analogue after numerous complexes, with thymine and guanine analogues have been reported. The adenine, analogue constitutes a new lead compound for enzyme-prodrug gene therapy., In addition, the structure of mutant Q125N modifying the binding site of, the natural substrate thymidine in complex with this substrate has been, established at 2.5 A resolution. It reveals that neither the binding mode, of thymidine nor the polypeptide backbone conformation is altered, except, that the two major hydrogen bonds to thymidine are replaced by a single, water-mediated hydrogen bond, which improves the relative acceptance of, the prodrugs aciclovir and ganciclovir compared with the natural, substrate. Accordingly, the mutant structure represents a first step, toward improving the virus-directed enzyme-prodrug gene therapy by enzyme, engineering.
About this StructureAbout this Structure
1E2J is a Single protein structure of sequence from Human herpesvirus 4 with SO4 and THM as ligands. Active as Thymidine kinase, with EC number 2.7.1.21 Full crystallographic information is available from OCA.
ReferenceReference
Nucleoside binding site of herpes simplex type 1 thymidine kinase analyzed by X-ray crystallography., Vogt J, Perozzo R, Pautsch A, Prota A, Schelling P, Pilger B, Folkers G, Scapozza L, Schulz GE, Proteins. 2000 Dec 1;41(4):545-53. PMID:11056041
Page seeded by OCA on Tue Nov 20 13:44:49 2007