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1r49

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[[Image:1r49.gif|left|200px]]
 
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{{Structure
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==Human topoisomerase I (Topo70) double mutant K532R/Y723F==
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|PDB= 1r49 |SIZE=350|CAPTION= <scene name='initialview01'>1r49</scene>, resolution 3.13&Aring;
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<StructureSection load='1r49' size='340' side='right'caption='[[1r49]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=DA:2&#39;-DEOXYADENOSINE-5&#39;-MONOPHOSPHATE'>DA</scene>, <scene name='pdbligand=DC:2&#39;-DEOXYCYTIDINE-5&#39;-MONOPHOSPHATE'>DC</scene>, <scene name='pdbligand=DG:2&#39;-DEOXYGUANOSINE-5&#39;-MONOPHOSPHATE'>DG</scene>, <scene name='pdbligand=DT:THYMIDINE-5&#39;-MONOPHOSPHATE'>DT</scene>
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<table><tr><td colspan='2'>[[1r49]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1R49 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1R49 FirstGlance]. <br>
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_topoisomerase DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.2 5.99.1.2] </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]] 3.13&#8491;</td></tr>
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|GENE= TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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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=1r49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1r49 OCA], [https://pdbe.org/1r49 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1r49 RCSB], [https://www.ebi.ac.uk/pdbsum/1r49 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1r49 ProSAT]</span></td></tr>
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|DOMAIN=
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</table>
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|RELATEDENTRY=[[1a36|1A36]], [[1ej9|1EJ9]], [[1k4s|1K4S]], [[1k4t|1K4T]], [[1lpq|1LPQ]], [[1tmc|1TMC]]
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== Disease ==
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1r49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1r49 OCA], [http://www.ebi.ac.uk/pdbsum/1r49 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1r49 RCSB]</span>
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[https://www.uniprot.org/uniprot/TOP1_HUMAN TOP1_HUMAN] Note=A chromosomal aberration involving TOP1 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with NUP98.
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}}
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== Function ==
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[https://www.uniprot.org/uniprot/TOP1_HUMAN TOP1_HUMAN] Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:2833744</ref> <ref>PMID:19168442</ref> <ref>PMID:14594810</ref> <ref>PMID:16033260</ref>
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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/r4/1r49_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=1r49 ConSurf].
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<div style="clear:both"></div>
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'''Human topoisomerase I (Topo70) double mutant K532R/Y723F'''
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==See Also==
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*[[Topoisomerase 3D structures|Topoisomerase 3D structures]]
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== References ==
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==Overview==
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<references/>
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Based on co-crystal structures of human topoisomerase I with bound DNA, Lys(532) makes a minor groove contact with the strongly preferred thymidine residue at the site of covalent attachment (-1 position). Replacement of Lys(532) with either arginine or alanine has essentially no effect on the sequence preference of the enzyme, indicating that this interaction is not required for the preference for a T at the -1 position. Although both the cleavage and religation activities of the K532R mutant enzyme are reduced, cleavage is reduced to a greater extent than religation. The reverse is true for the K532A mutant enzyme with religation so impaired that the nicked intermediate accumulates during plasmid relaxation assays. Consistent with the shift in the cleavage religation equilibrium toward cleavage for the K532A mutant enzyme, expression of the mutant enzyme in Saccharomyces cerevisiae is cytotoxic, and thus this mutant enzyme mimics the effects of the anticancer drug camptothecin. Cleavage assays with the mutant enzymes using an oligonucleotide containing a 5'-bridging phosphorothiolate indicate that Lys(532) functions as a general acid during cleavage to protonate the leaving 5'-oxygen. It is possible that the contact with the -1 base is important during catalysis to provide positional rigidity to the active site. The corresponding residues in the vaccinia virus topoisomerase and the tyrosine recombinases may have similar critical roles in catalysis.
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__TOC__
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</StructureSection>
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==Disease==
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Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126420 126420]]
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==About this Structure==
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1R49 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1R49 OCA].
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==Reference==
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The role of lysine 532 in the catalytic mechanism of human topoisomerase I., Interthal H, Quigley PM, Hol WG, Champoux JJ, J Biol Chem. 2004 Jan 23;279(4):2984-92. Epub 2003 Oct 31. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14594810 14594810]
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[[Category: DNA topoisomerase]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Champoux, J J.]]
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[[Category: Champoux JJ]]
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[[Category: Hol, W G.]]
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[[Category: Hol WG]]
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[[Category: Interthal, H.]]
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[[Category: Interthal H]]
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[[Category: Quigley, P M.]]
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[[Category: Quigley PM]]
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[[Category: dna]]
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[[Category: protein]]
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[[Category: topoisomerase i]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:22:58 2008''
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Current revision

Human topoisomerase I (Topo70) double mutant K532R/Y723F

PDB ID 1r49

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