1e2h: Difference between revisions
New page: left|200px<br /><applet load="1e2h" size="450" color="white" frame="true" align="right" spinBox="true" caption="1e2h, resolution 1.9Å" /> '''THE NUCLEOSIDE BINDIN... |
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[[Image:1e2h.gif|left|200px]]<br /><applet load="1e2h" size=" | [[Image:1e2h.gif|left|200px]]<br /><applet load="1e2h" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1e2h, resolution 1.9Å" /> | caption="1e2h, resolution 1.9Å" /> | ||
'''THE NUCLEOSIDE BINDING SITE OF HERPES SIMPLEX TYPE 1 THYMIDINE KINASE ANALYZED BY X-RAY CRYSTALLOGRAPHY'''<br /> | '''THE NUCLEOSIDE BINDING SITE OF HERPES SIMPLEX TYPE 1 THYMIDINE KINASE ANALYZED BY X-RAY CRYSTALLOGRAPHY'''<br /> | ||
==Overview== | ==Overview== | ||
The crystal structures of the full-length Herpes simplex virus type 1 | 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 Structure== | ==About this Structure== | ||
1E2H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_herpesvirus_4 Human herpesvirus 4] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thymidine_kinase Thymidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.21 2.7.1.21] Full crystallographic information is available from [http:// | 1E2H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_herpesvirus_4 Human herpesvirus 4] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thymidine_kinase Thymidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.21 2.7.1.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E2H OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Thymidine kinase]] | [[Category: Thymidine kinase]] | ||
[[Category: Scapozza, L.]] | [[Category: Scapozza, L.]] | ||
[[Category: Schulz, G | [[Category: Schulz, G E.]] | ||
[[Category: Vogt, J.]] | [[Category: Vogt, J.]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: x-ray crystallography]] | [[Category: x-ray crystallography]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:23:03 2008'' | ||
Revision as of 13:23, 21 February 2008
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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
1E2H is a Single protein structure of sequence from Human herpesvirus 4 with as ligand. 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
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