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1e2k

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Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)-methanocarba-thymidine

Structural highlights

1e2k is a 2 chain structure with sequence from Human alphaherpesvirus 1 strain 17. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.7Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KITH_HHV11 In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate their genome (By similarity).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Kinetic and crystallographic analyses of wild-type Herpes simplex virus type 1 thymidine kinase (TK(HSV1)) and its Y101F-mutant [TK(HSV1)(Y101F)] acting on the potent antiviral drug 2'-exo-methanocarba-thymidine (MCT) have been performed. The kinetic study reveals a 12-fold K(M) increase for thymidine processed with Y101F as compared to the wild-type TK(HSV1). Furthermore, MCT is a substrate for both wild-type and mutant TK(HSV1). Its binding affinity for TK(HSV1) and TK(HSV1)(Y101F), expressed as K(i), is 11 microM and 51 microM, respectively, whereas the K(i) for human cytosolic thymidine kinase is as high as 1.6 mM, rendering TK(HSV1) a selectivity filter for antiviral activity. Moreover, TK(HSV1)(Y101F) shows a decrease in the quotient of the catalytic efficiency (k(cat)/K(M)) of dT over MCT corresponding to an increased specificity for MCT when compared to the wild-type enzyme. Crystal structures of wild-type and mutant TK(HSV1) in complex with MCT have been determined to resolutions of 1.7 and 2.4 A, respectively. The thymine moiety of MCT binds like the base of dT while the conformationally restricted bicyclo[3.1.0]hexane, mimicking the sugar moiety, assumes a 2'-exo envelope conformation that is flatter than the one observed for the free compound. The hydrogen bond pattern around the sugar-like moiety differs from that of thymidine, revealing the importance of the rigid conformation of MCT with respect to hydrogen bonds. These findings make MCT a lead compound in the design of resistance-repellent drugs for antiviral therapy, and mutant Y101F, in combination with MCT, opens new possibilities for gene therapy.

Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)-methanocarba-thymidine.,Prota A, Vogt J, Pilger B, Perozzo R, Wurth C, Marquez VE, Russ P, Schulz GE, Folkers G, Scapozza L Biochemistry. 2000 Aug 8;39(31):9597-603. PMID:10924157^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Prota A, Vogt J, Pilger B, Perozzo R, Wurth C, Marquez VE, Russ P, Schulz GE, Folkers G, Scapozza L. Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)-methanocarba-thymidine. Biochemistry. 2000 Aug 8;39(31):9597-603. PMID:10924157

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1e2k"

Categories: Human alphaherpesvirus 1 strain 17 | Large Structures | Scapozza L | Schulz GE | Vogt J

@@ Line 3: / Line 3: @@
 <StructureSection load='1e2k' size='340' side='right'caption='[[1e2k]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1e2k]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E2K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1E2K FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1e2k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_alphaherpesvirus_1_strain_17 Human alphaherpesvirus 1 strain 17]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E2K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E2K FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TMC:1-[4-HYDROXY-5-(HYDROXYMETHYL)BICYCLO[3.1.0]HEX-2-YL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>TMC</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1kim|1kim]], [[1vtk|1vtk]], [[2vtk|2vtk]], [[3vtk|3vtk]], [[1ki2|1ki2]], [[1ki4|1ki4]], [[1ki5|1ki5]], [[1ki6|1ki6]], [[1ki7|1ki7]], [[1ki8|1ki8]], [[1e2j|1e2j]], [[1e2h|1e2h]], [[1e2i|1e2i]], [[1e2l|1e2l]], [[1e2m|1e2m]], [[1e2n|1e2n]], [[1e2p|1e2p]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TMC:1-[4-HYDROXY-5-(HYDROXYMETHYL)BICYCLO[3.1.0]HEX-2-YL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>TMC</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1e2k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e2k OCA], [https://pdbe.org/1e2k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e2k RCSB], [https://www.ebi.ac.uk/pdbsum/1e2k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e2k ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e2k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e2k OCA], [http://pdbe.org/1e2k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1e2k RCSB], [http://www.ebi.ac.uk/pdbsum/1e2k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1e2k ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/KITH_HHV11 KITH_HHV11]] In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate their genome (By similarity).
+[https://www.uniprot.org/uniprot/KITH_HHV11 KITH_HHV11] In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate their genome (By similarity).
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 32: / Line 31: @@
 ==See Also==
-*[[Thymidine kinase|Thymidine kinase]]
+*[[Thymidine kinase 3D structures|Thymidine kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human alphaherpesvirus 1 strain 17]]
 [[Category: Large Structures]]
-[[Category: Thymidine kinase]]
+[[Category: Scapozza L]]
-[[Category: Scapozza, L]]
+[[Category: Schulz GE]]
-[[Category: Schulz, G E]]
+[[Category: Vogt J]]
-[[Category: Vogt, J]]
-[[Category: Antiviral drug]]
-[[Category: Enzyme-prodrug gene therapy]]
-[[Category: Sugar ring pucker]]
-[[Category: Transferase]]

1e2k

From Proteopedia

Current revision

Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)-methanocarba-thymidine

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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