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| | <StructureSection load='5ujy' size='340' side='right'caption='[[5ujy]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='5ujy' size='340' side='right'caption='[[5ujy]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ujy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UJY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UJY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ujy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UJY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UJY FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5d5h|5d5h]], [[5uj1|5uj1]], [[5ukt|5ukt]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">topA_1, topA, BN1213_00605, BN1303_02614, ERS013471_01645, ERS027644_01463, ERS124361_02532, RN05_3882 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=5ujy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ujy OCA], [https://pdbe.org/5ujy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ujy RCSB], [https://www.ebi.ac.uk/pdbsum/5ujy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ujy ProSAT]</span></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=5ujy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ujy OCA], [http://pdbe.org/5ujy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ujy RCSB], [http://www.ebi.ac.uk/pdbsum/5ujy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ujy ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/A0A0E8VY41_MYCTX A0A0E8VY41_MYCTX]] Releases the supercoiling and torsional tension of DNA, which is 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-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-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 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone.[HAMAP-Rule:MF_00952] | + | [https://www.uniprot.org/uniprot/TOP1_MYCTU TOP1_MYCTU] Releases the supercoiling and torsional tension of DNA, which is 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-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-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 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone.[HAMAP-Rule:MF_00952]<ref>PMID:20724443</ref> The C-terminus (residues 622-934) inhibits RNA cleavage by MazF4.<ref>PMID:20724443</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Topoisomerase|Topoisomerase]] | + | *[[Topoisomerase 3D structures|Topoisomerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA topoisomerase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cao, N]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Tan, K]] | + | [[Category: Cao N]] |
| - | [[Category: Tse-Dinh, Y C]] | + | [[Category: Tan K]] |
| - | [[Category: Dna topoisomerase i]]
| + | [[Category: Tse-Dinh YC]] |
| - | [[Category: Isomerase]]
| + | |
| Structural highlights
Function
TOP1_MYCTU Releases the supercoiling and torsional tension of DNA, which is 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-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-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 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone.[HAMAP-Rule:MF_00952][1] The C-terminus (residues 622-934) inhibits RNA cleavage by MazF4.[2]
Publication Abstract from PubMed
We have obtained new crystal structures of Mycobacterium tuberculosis topoisomerase I, including structures with ssDNA substrate bound to the active site, with and without Mg2+ ion present. Significant enzyme conformational changes upon DNA binding place the catalytic tyrosine in a pre-transition state position for cleavage of a specific phosphodiester linkage. Meanwhile, the enzyme/DNA complex with bound Mg2+ ion may represent the post-transition state for religation in the enzyme's multiple-step DNA relaxation catalytic cycle. The first observation of Mg2+ ion coordinated with the TOPRIM residues and DNA phosphate in a type IA topoisomerase active site allows assignment of likely catalytic role for the metal and draws a comparison to the proposed mechanism for type IIA topoisomerases. The critical function of a strictly conserved glutamic acid in the DNA cleavage step was assessed through site-directed mutagenesis. The functions assigned to the observed Mg2+ ion can account for the metal requirement for DNA rejoining but not DNA cleavage by type IA topoisomerases. This work provides new structural insights into a more stringent requirement for DNA rejoining versus cleavage in the catalytic cycle of this essential enzyme, and further establishes the potential for selective interference of DNA rejoining by this validated TB drug target.
Investigating mycobacterial topoisomerase I mechanism from the analysis of metal and DNA substrate interactions at the active site.,Cao N, Tan K, Annamalai T, Joachimiak A, Tse-Dinh YC Nucleic Acids Res. 2018 Jun 14. pii: 5037723. doi: 10.1093/nar/gky492. PMID:29905859[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Huang F, He ZG. Characterization of an interplay between a Mycobacterium tuberculosis MazF homolog, Rv1495 and its sole DNA topoisomerase I. Nucleic Acids Res. 2010 Dec;38(22):8219-30. doi: 10.1093/nar/gkq737. Epub 2010, Aug 19. PMID:20724443 doi:http://dx.doi.org/10.1093/nar/gkq737
- ↑ Huang F, He ZG. Characterization of an interplay between a Mycobacterium tuberculosis MazF homolog, Rv1495 and its sole DNA topoisomerase I. Nucleic Acids Res. 2010 Dec;38(22):8219-30. doi: 10.1093/nar/gkq737. Epub 2010, Aug 19. PMID:20724443 doi:http://dx.doi.org/10.1093/nar/gkq737
- ↑ Cao N, Tan K, Annamalai T, Joachimiak A, Tse-Dinh YC. Investigating mycobacterial topoisomerase I mechanism from the analysis of metal and DNA substrate interactions at the active site. Nucleic Acids Res. 2018 Jun 14. pii: 5037723. doi: 10.1093/nar/gky492. PMID:29905859 doi:http://dx.doi.org/10.1093/nar/gky492
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