1rrj: Difference between revisions

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-[[Image:1rrj.png|left|200px]]
-{{STRUCTURE_1rrj|  PDB=1rrj  |  SCENE=  }}
+==Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I==
+<StructureSection load='1rrj' size='340' side='right'caption='[[1rrj]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1rrj]] 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=1RRJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RRJ FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=TTC:(S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-DIHYDROXY-1H-PYRANO[3,4 6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE'>TTC</scene>, <scene name='pdbligand=TTG:2-(1-DIMETHYLAMINOMETHYL-2-HYDROXY-8-HYDROXYMETHYL-9-OXO-9,11-DIHYDRO-INDOLIZINO[1,2-B]QUINOLIN-7-YL)-2-HYDROXY-BUTYRIC+ACID'>TTG</scene></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=1rrj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rrj OCA], [https://pdbe.org/1rrj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rrj RCSB], [https://www.ebi.ac.uk/pdbsum/1rrj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rrj ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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.
+== Function ==
+[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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rr/1rrj_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=1rrj ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Human topoisomerase I relaxes superhelical tension associated with DNA replication, transcription and recombination by reversibly nicking one strand of duplex DNA and forming a covalent 3'-phosphotyrosine linkage. This enzyme is the sole target of the camptothecin family of anticancer compounds, which acts by stabilizing the covalent protein-DNA complex and enhancing apoptosis through blocking the advancement of replication forks. Mutations that impart resistance to camptothecin have been identified in several regions of human topoisomerase I. We present the crystal structures of two camptothecin-resistant forms of human topoisomerase I (Phe361Ser at 2.6A resolution and Asn722Ser at 2.3A resolution) in ternary complexes with DNA and topotecan (Hycamtin), a camptothecin analogue currently in widespread clinical use. While the alteration of Asn722 to Ser leads to the elimination of a water-mediated contact between the enzyme and topotecan, we were surprised to find that a well-ordered water molecule replaces the hydrophobic phenylalanine side-chain in the Phe361Ser structure. We further consider camptothecin-resistant mutations at seven additional sites in human topoisomerase I and present structural evidence explaining their possible impact on drug binding. These results advance our understanding of the mechanism of cell poisoning by camptothecin and suggest specific modifications to the drug that may improve efficacy.
-===Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I===
+Mechanisms of camptothecin resistance by human topoisomerase I mutations.,Chrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, Redinbo MR J Mol Biol. 2004 Jun 11;339(4):773-84. PMID:15165849<ref>PMID:15165849</ref>
-{{ABSTRACT_PUBMED_15165849}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 1rrj" style="background-color:#fffaf0;"></div>
-[[1rrj]] is a 3 chain structure of [[Topoisomerase]] with 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=1RRJ OCA].
 ==See Also==
-*[[Topoisomerase|Topoisomerase]]
+*[[Topoisomerase 3D structures|Topoisomerase 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:015165849</ref><references group="xtra"/>
+__TOC__
-[[Category: DNA topoisomerase]]
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Burgin, A B.]]
+[[Category: Large Structures]]
-[[Category: Chrencik, J E.]]
+[[Category: Burgin AB]]
-[[Category: Redinbo, M R.]]
+[[Category: Chrencik JE]]
-[[Category: Staker, B L.]]
+[[Category: Redinbo MR]]
-[[Category: Stewart, L.]]
+[[Category: Staker BL]]
-[[Category: Camptothecin]]
+[[Category: Stewart L]]
-[[Category: Human topoisomerase i]]
-[[Category: Isomerase-dna complex]]
-[[Category: Topotecan]]