1k4s

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(New page: 200px<br /> <applet load="1k4s" size="450" color="white" frame="true" align="right" spinBox="true" caption="1k4s, resolution 3.20&Aring;" /> '''HUMAN DNA TOPOISOME...)
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[[Image:1k4s.gif|left|200px]]<br />
 
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<applet load="1k4s" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1k4s, resolution 3.20&Aring;" />
 
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'''HUMAN DNA TOPOISOMERASE I IN COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX'''<br />
 
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==Overview==
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==HUMAN DNA TOPOISOMERASE I IN COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX==
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We report the x-ray crystal structure of human topoisomerase I covalently, joined to double-stranded DNA and bound to the clinically approved, anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at, the site of DNA cleavage by intercalating between the upstream (-1) and, downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding, to the enzyme-substrate complex, Topotecan acts as an uncompetitive, inhibitor. The structure can explain several of the known, structure-activity relationships of the camptothecin family of anticancer, drugs and suggests that there are at least two classes of mutations that, can produce a drug-resistant enzyme. The first class includes changes to, residues that contribute to direct interactions with the drug, whereas a, second class would alter interactions with the DNA and thereby destabilize, the drug-binding site.
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<StructureSection load='1k4s' size='340' side='right'caption='[[1k4s]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1k4s]] is a 4 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=1K4S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1K4S FirstGlance]. <br>
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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]] 3.2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5IU:5-IODO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>5IU</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SPT:5-THIO-THYMIDINE+PHOSPHONIC+ACID'>SPT</scene></td></tr>
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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=1k4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1k4s OCA], [https://pdbe.org/1k4s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1k4s RCSB], [https://www.ebi.ac.uk/pdbsum/1k4s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1k4s ProSAT]</span></td></tr>
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</table>
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== Disease ==
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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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== 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/k4/1k4s_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1k4s 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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We report the x-ray crystal structure of human topoisomerase I covalently joined to double-stranded DNA and bound to the clinically approved anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (-1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme-substrate complex, Topotecan acts as an uncompetitive inhibitor. The structure can explain several of the known structure-activity relationships of the camptothecin family of anticancer drugs and suggests that there are at least two classes of mutations that can produce a drug-resistant enzyme. The first class includes changes to residues that contribute to direct interactions with the drug, whereas a second class would alter interactions with the DNA and thereby destabilize the drug-binding site.
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==Disease==
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The mechanism of topoisomerase I poisoning by a camptothecin analog.,Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. PMID:12426403<ref>PMID:12426403</ref>
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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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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1K4S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1K4S OCA].
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</div>
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<div class="pdbe-citations 1k4s" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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The mechanism of topoisomerase I poisoning by a camptothecin analog., Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L, Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12426403 12426403]
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*[[Topoisomerase 3D structures|Topoisomerase 3D structures]]
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[[Category: DNA topoisomerase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[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: Behnke, C.A.]]
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[[Category: Behnke CA]]
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[[Category: Feese, M.D.]]
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[[Category: Burgin Jr AB]]
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[[Category: Hjerrild, K.]]
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[[Category: Feese MD]]
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[[Category: Jr., A.B.Burgin.]]
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[[Category: Hjerrild K]]
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[[Category: Staker, B.L.]]
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[[Category: Staker BL]]
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[[Category: Stewart, L.J.]]
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[[Category: Stewart LJ]]
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[[Category: complex (isomerase/dna)]]
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[[Category: dna]]
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[[Category: topoisomerase i]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:47:14 2007''
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Current revision

HUMAN DNA TOPOISOMERASE I IN COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX

PDB ID 1k4s

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