1of1

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[[Image:1of1.jpg|left|200px]]
 
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{{Structure
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==KINETICS AND CRYSTAL STRUCTURE OF THE HERPES SIMPLEX VIRUS TYPE 1 THYMIDINE KINASE INTERACTING WITH (SOUTH)-METHANOCARBA-THYMIDINE==
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|PDB= 1of1 |SIZE=350|CAPTION= <scene name='initialview01'>1of1</scene>, resolution 1.95&Aring;
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<StructureSection load='1of1' size='340' side='right'caption='[[1of1]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+B'>AC1</scene>
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=SCT:(SOUTH)-METHANOCARBA-THYMIDINE'>SCT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
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<table><tr><td colspan='2'>[[1of1]] 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=1OF1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1OF1 FirstGlance]. <br>
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|ACTIVITY= <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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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|GENE=
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SCT:(SOUTH)-METHANOCARBA-THYMIDINE'>SCT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1of1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1of1 OCA], [https://pdbe.org/1of1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1of1 RCSB], [https://www.ebi.ac.uk/pdbsum/1of1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1of1 ProSAT]</span></td></tr>
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|RELATEDENTRY=
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1of1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1of1 OCA], [http://www.ebi.ac.uk/pdbsum/1of1 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1of1 RCSB]</span>
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== Function ==
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}}
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[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).
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/of/1of1_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1of1 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Two analogs of the natural nucleoside dT featuring a pseudosugar with fixed conformation in place of the deoxyribosyl residue (carbathymidine analogs) were biochemically and structurally characterized for their acceptance by both human cytosolic thymidine kinase isoenzyme 1 (hTK1) and herpes simplex virus type 1 thymidine kinase (HSV1 TK) and subsequently tested in cell proliferation assays. 3'-exo-Methanocarbathymidine ((South)-methanocarbathymidine (S)-MCT), which is a substrate for HSV1 TK, specifically inhibited growth of HSV1 TK-transduced human osteosarcoma cells with an IC(50) value in the range of 15 microM without significant toxicity toward both hTK1-negative (TK(-)) and non-transduced cells. 2'-exo-Methanocarbathymidine ((North)-methanocarbathymidine (N)-MCT), which is a weak substrate for hTK1 and a substantial one for HSV1 TK, induced a specific growth inhibition in HSV1 TK-transfected cells comparable to that of (S)-MCT and ganciclovir. A growth inhibition activity was also observed with (N)-MCT and ganciclovir in non-transduced cells in a cell line-dependent manner, whereas TK(-) cells were not affected. The presented 1.95-A crystal structure of the complex (S)-MCT.HSV1 TK explains both the more favorable binding affinity and catalytic turnover of (S)-MCT for HSV1 TK over the North analog. Additionally the plasticity of the active site of the enzyme is addressed by comparing the binding of (North)- and (South)-carbathymidine analogs. The presented study of these two potent candidate prodrugs for HSV1 TK gene-directed enzyme prodrug therapy suggests that (S)-MCT may be even safer to use than its North counterpart (N)-MCT.
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'''KINETICS AND CRYSTAL STRUCTURE OF THE HERPES SIMPLEX VIRUS TYPE 1 THYMIDINE KINASE INTERACTING WITH (SOUTH)-METHANOCARBA-THYMIDINE'''
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Biochemical and structural characterization of (South)-methanocarbathymidine that specifically inhibits growth of herpes simplex virus type 1 thymidine kinase-transduced osteosarcoma cells.,Schelling P, Claus MT, Johner R, Marquez VE, Schulz GE, Scapozza L J Biol Chem. 2004 Jul 30;279(31):32832-8. Epub 2004 May 25. PMID:15163659<ref>PMID:15163659</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 1of1" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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Chondroitinase B from Pedobacter heparinus is the only known enzyme strictly specific for dermatan sulfate and is a widely used enzymatic tool for the structural characterization of glycosaminoglycans. This beta-helical polysaccharide lyase belongs to family PL-6 and cleaves the beta(1,4) linkage of dermatan sulfate in a random manner, yielding 4,5-unsaturated dermatan sulfate disaccharides as the product. The previously reported structure of its complex with a dermatan sulfate disaccharide product identified the -1 and -2 subsites of the catalytic groove. We present here the structure of chondroitinase B complexed with several dermatan sulfate and chondroitin sulfate oligosaccharides. In particular, the soaking of chondroitinase B crystals with a dermatan sulfate hexasaccharide results in a complex with two dermatan sulfate disaccharide reaction products, enabling the identification of the +2 and +1 subsites. Unexpectedly, this structure revealed the presence of a calcium ion coordinated by sequence-conserved acidic residues and by the carboxyl group of the l-iduronic acid at the +1 subsite. Kinetic and site-directed mutagenesis experiments have subsequently demonstrated that chondroitinase B absolutely requires calcium for its activity, indicating that the protein-Ca(2+)-oligosaccharide complex is functionally relevant. Modeling of an intact tetrasaccharide in the active site of chondroitinase B provided a better understanding of substrate specificity and the role of Ca(2+) in enzymatic activity. Given these results, we propose that the Ca(2+) ion neutralizes the carboxyl moiety of the l-iduronic acid at the cleavage site, whereas the conserved residues Lys-250 and Arg-271 act as Bronsted base and acid, respectively, in the lytic degradation of dermatan sulfate by chondroitinase B.
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*[[Thymidine kinase 3D structures|Thymidine kinase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1OF1 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_herpesvirus_1 Human herpesvirus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OF1 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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[[Category: Human alphaherpesvirus 1 strain 17]]
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The structure of chondroitin B lyase complexed with glycosaminoglycan oligosaccharides unravels a calcium-dependent catalytic machinery., Michel G, Pojasek K, Li Y, Sulea T, Linhardt RJ, Raman R, Prabhakar V, Sasisekharan R, Cygler M, J Biol Chem. 2004 Jul 30;279(31):32882-96. Epub 2004 May 21. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15155751 15155751]
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[[Category: Large Structures]]
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[[Category: Human herpesvirus 1]]
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[[Category: Claus MT]]
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[[Category: Single protein]]
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[[Category: Folkers G]]
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[[Category: Thymidine kinase]]
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[[Category: Marquez VE]]
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[[Category: Claus, M T.]]
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[[Category: Scapozza L]]
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[[Category: Folkers, G.]]
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[[Category: Schelling P]]
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[[Category: Marquez, V E.]]
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[[Category: Schulz GE]]
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[[Category: Scapozza, L.]]
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[[Category: Schelling, P.]]
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[[Category: Schulz, G E.]]
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[[Category: antiviral drug]]
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[[Category: atp-binding]]
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[[Category: dna synthesis]]
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[[Category: enzyme-prodrug gene]]
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[[Category: kinase]]
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[[Category: thymidine kinase]]
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[[Category: transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:44:23 2008''
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Current revision

KINETICS AND CRYSTAL STRUCTURE OF THE HERPES SIMPLEX VIRUS TYPE 1 THYMIDINE KINASE INTERACTING WITH (SOUTH)-METHANOCARBA-THYMIDINE

PDB ID 1of1

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