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1rr8

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Revision as of 02:54, 10 September 2015

Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I

Structural highlights

1rr8 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:	,
Gene:	TOP1 (HUMAN)
Activity:	DNA topoisomerase, with EC number 5.99.1.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[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

[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.^[1] ^[2] ^[3] ^[4]

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

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.

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^[5]

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

References

↑ D'Arpa P, Machlin PS, Ratrie H 3rd, Rothfield NF, Cleveland DW, Earnshaw WC. cDNA cloning of human DNA topoisomerase I: catalytic activity of a 67.7-kDa carboxyl-terminal fragment. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2543-7. PMID:2833744
↑ Eisenreich A, Bogdanov VY, Zakrzewicz A, Pries A, Antoniak S, Poller W, Schultheiss HP, Rauch U. Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. Circ Res. 2009 Mar 13;104(5):589-99. doi: 10.1161/CIRCRESAHA.108.183905. Epub, 2009 Jan 22. PMID:19168442 doi:10.1161/CIRCRESAHA.108.183905
↑ Interthal H, Quigley PM, Hol WG, Champoux JJ. The role of lysine 532 in the catalytic mechanism of human topoisomerase I. J Biol Chem. 2004 Jan 23;279(4):2984-92. Epub 2003 Oct 31. PMID:14594810 doi:10.1074/jbc.M309959200
↑ Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M. Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis. J Med Chem. 2005 Jul 28;48(15):4803-14. PMID:16033260 doi:10.1021/jm050076b
↑ Chrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, Redinbo MR. Mechanisms of camptothecin resistance by human topoisomerase I mutations. J Mol Biol. 2004 Jun 11;339(4):773-84. PMID:15165849 doi:http://dx.doi.org/10.1016/j.jmb.2004.03.077

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1rr8"

@@ Line 2: / Line 2: @@
 <StructureSection load='1rr8' size='340' side='right' caption='[[1rr8]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1rr8]] is a 3 chain structure 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=1RR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1RR8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1rr8]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1RR8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><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></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></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=1rr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rr8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1rr8 RCSB], [http://www.ebi.ac.uk/pdbsum/1rr8 PDBsum]</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=1rr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rr8 OCA], [http://pdbe.org/1rr8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1rr8 RCSB], [http://www.ebi.ac.uk/pdbsum/1rr8 PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 31: / Line 31: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1rr8" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 39: / Line 40: @@
 </StructureSection>
 [[Category: DNA topoisomerase]]
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Burgin, A B]]
 [[Category: Chrencik, J E]]

1rr8

From Proteopedia

Revision as of 02:54, 10 September 2015

Structural Mechanisms of Camptothecin Resistance by Mutations in Human Topoisomerase I

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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