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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2000-12-11
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenine,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Monophosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Nucleosides,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphonic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Prodrugs,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Viral Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Water,
http://linkedlifedata.com/resource/pubmed/chemical/adefovir
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0887-3585
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
545-53
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pubmed:dateRevised |
2004-11-17
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pubmed:meshHeading |
pubmed-meshheading:11056041-Adenine,
pubmed-meshheading:11056041-Adenosine,
pubmed-meshheading:11056041-Adenosine Monophosphate,
pubmed-meshheading:11056041-Amino Acid Substitution,
pubmed-meshheading:11056041-Antiviral Agents,
pubmed-meshheading:11056041-Binding Sites,
pubmed-meshheading:11056041-Catalytic Domain,
pubmed-meshheading:11056041-Crystallography, X-Ray,
pubmed-meshheading:11056041-Enzyme Inhibitors,
pubmed-meshheading:11056041-Herpesvirus 1, Human,
pubmed-meshheading:11056041-Mutation,
pubmed-meshheading:11056041-Nucleosides,
pubmed-meshheading:11056041-Phosphonic Acids,
pubmed-meshheading:11056041-Prodrugs,
pubmed-meshheading:11056041-Protein Structure, Tertiary,
pubmed-meshheading:11056041-Stereoisomerism,
pubmed-meshheading:11056041-Substrate Specificity,
pubmed-meshheading:11056041-Thymidine,
pubmed-meshheading:11056041-Thymidine Kinase,
pubmed-meshheading:11056041-Viral Proteins,
pubmed-meshheading:11056041-Water
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pubmed:year |
2000
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pubmed:articleTitle |
Nucleoside binding site of herpes simplex type 1 thymidine kinase analyzed by X-ray crystallography.
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pubmed:affiliation |
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Freiburg im Breisgau, Germany.
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pubmed:publicationType |
Journal Article
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