1ki4: Difference between revisions

Revision as of 14:34, 21 February 2008

CRYSTAL STRUCTURE OF THYMIDINE KINASE FROM HERPES SIMPLEX VIRUS TYPE I COMPLEXED WITH 5-BROMOTHIENYLDEOXYURIDINE

OverviewOverview

Antiherpes therapies are principally targeted at viral thymidine kinases and utilize nucleoside analogs, the triphosphates of which are inhibitors of viral DNA polymerase or result in toxic effects when incorporated into DNA. The most frequently used drug, aciclovir (Zovirax), is a relatively poor substrate for thymidine kinase and high-resolution structural information on drugs and other molecules binding to the target is therefore important for the design of novel and more potent chemotherapy, both in antiherpes treatment and in gene therapy systems where thymidine kinase is expressed. Here, we report for the first time the binary complexes of HSV-1 thymidine kinase (TK) with the drug molecules aciclovir and penciclovir, determined by X-ray crystallography at 2.37 A resolution. Moreover, from new data at 2.14 A resolution, the refined structure of the complex of TK with its substrate deoxythymidine (R = 0.209 for 96% of all data) now reveals much detail concerning substrate and solvent interactions with the enzyme. Structures of the complexes of TK with four halogen-containing substrate analogs have also been solved, to resolutions better than 2.4 A. The various TK inhibitors broadly fall into three groups which together probe the space of the enzyme active site in a manner that no one molecule does alone, so giving a composite picture of active site interactions that can be exploited in the design of novel compounds.

About this StructureAbout this Structure

1KI4 is a Single protein structure of sequence from Human herpesvirus 4 with and as ligands. Active as Thymidine kinase, with EC number 2.7.1.21 Full crystallographic information is available from OCA.

ReferenceReference

Exploring the active site of herpes simplex virus type-1 thymidine kinase by X-ray crystallography of complexes with aciclovir and other ligands., Champness JN, Bennett MS, Wien F, Visse R, Summers WC, Herdewijn P, de Clerq E, Ostrowski T, Jarvest RL, Sanderson MR, Proteins. 1998 Aug 15;32(3):350-61. PMID:9715911

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-[[Image:1ki4.gif|left|200px]]<br /><applet load="1ki4" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1ki4.gif|left|200px]]<br /><applet load="1ki4" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1ki4, resolution 2.34&Aring;" />
 '''CRYSTAL STRUCTURE OF THYMIDINE KINASE FROM HERPES SIMPLEX VIRUS TYPE I COMPLEXED WITH 5-BROMOTHIENYLDEOXYURIDINE'''<br />
 ==Overview==
-Antiherpes therapies are principally targeted at viral thymidine kinases, and utilize nucleoside analogs, the triphosphates of which are inhibitors, of viral DNA polymerase or result in toxic effects when incorporated into, DNA. The most frequently used drug, aciclovir (Zovirax), is a relatively, poor substrate for thymidine kinase and high-resolution structural, information on drugs and other molecules binding to the target is, therefore important for the design of novel and more potent chemotherapy, both in antiherpes treatment and in gene therapy systems where thymidine, kinase is expressed. Here, we report for the first time the binary, complexes of HSV-1 thymidine kinase (TK) with the drug molecules aciclovir, and penciclovir, determined by X-ray crystallography at 2.37 A resolution., Moreover, from new data at 2.14 A resolution, the refined structure of the, complex of TK with its substrate deoxythymidine (R = 0.209 for 96% of all, data) now reveals much detail concerning substrate and solvent, interactions with the enzyme. Structures of the complexes of TK with four, halogen-containing substrate analogs have also been solved, to resolutions, better than 2.4 A. The various TK inhibitors broadly fall into three, groups which together probe the space of the enzyme active site in a, manner that no one molecule does alone, so giving a composite picture of, active site interactions that can be exploited in the design of novel, compounds.
+Antiherpes therapies are principally targeted at viral thymidine kinases and utilize nucleoside analogs, the triphosphates of which are inhibitors of viral DNA polymerase or result in toxic effects when incorporated into DNA. The most frequently used drug, aciclovir (Zovirax), is a relatively poor substrate for thymidine kinase and high-resolution structural information on drugs and other molecules binding to the target is therefore important for the design of novel and more potent chemotherapy, both in antiherpes treatment and in gene therapy systems where thymidine kinase is expressed. Here, we report for the first time the binary complexes of HSV-1 thymidine kinase (TK) with the drug molecules aciclovir and penciclovir, determined by X-ray crystallography at 2.37 A resolution. Moreover, from new data at 2.14 A resolution, the refined structure of the complex of TK with its substrate deoxythymidine (R = 0.209 for 96% of all data) now reveals much detail concerning substrate and solvent interactions with the enzyme. Structures of the complexes of TK with four halogen-containing substrate analogs have also been solved, to resolutions better than 2.4 A. The various TK inhibitors broadly fall into three groups which together probe the space of the enzyme active site in a manner that no one molecule does alone, so giving a composite picture of active site interactions that can be exploited in the design of novel compounds.
 ==About this Structure==
-KI4 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 and BTD as [http://en.wikipedia.org/wiki/ligands ligands]. 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1KI4 OCA].
+KI4 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> and <scene name='pdbligand=BTD:'>BTD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1KI4 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Thymidine kinase]]
-[[Category: Bennett, M.S.]]
+[[Category: Bennett, M S.]]
-[[Category: Champness, J.N.]]
+[[Category: Champness, J N.]]
-[[Category: Sanderson, M.R.]]
+[[Category: Sanderson, M R.]]
-[[Category: Summers, W.C.]]
+[[Category: Summers, W C.]]
 [[Category: Visse, R.]]
 [[Category: Wien, F.]]
@@ Line 31: / Line 31: @@
 [[Category: viridae]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 19:15:35 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:34:25 2008''