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==Crystal structure of the G-quadruplex formed by (GGGTT)3GGG in complex with N-methylmesoporphryin IX== | ==Crystal structure of the G-quadruplex formed by (GGGTT)3GGG in complex with N-methylmesoporphryin IX== | ||
<StructureSection load='6pnk' size='340' side='right'caption='[[6pnk]]' scene=''> | <StructureSection load='6pnk' size='340' side='right'caption='[[6pnk]], [[Resolution|resolution]] 2.39Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PNK OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6pnk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Tetrahymena_thermophila Tetrahymena thermophila]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PNK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PNK FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.39Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MMP:N-METHYLMESOPORPHYRIN'>MMP</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=6pnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pnk OCA], [https://pdbe.org/6pnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pnk RCSB], [https://www.ebi.ac.uk/pdbsum/6pnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pnk ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The G-quadruplex (GQ) is a well-studied non-canonical DNA structure formed by G-rich sequences found at telomeres and gene promoters. Biological studies suggest that GQs may play roles in regulating gene expression, DNA replication, and DNA repair. Small molecule ligands were shown to alter GQ structure and stability and thereby serve as novel therapies, particularly against cancer. In this work, we investigate the interaction of a G-rich sequence, 5'-GGGTTGGGTTGGGTTGGG-3' (T1), with a water-soluble porphyrin, N-methyl mesoporphyrin IX (NMM) via biophysical and X-ray crystallographic studies. UV-vis and fluorescence titrations, as well as a Job plot, revealed a 1:1 binding stoichiometry with an impressively tight binding constant of 30-50 muM-1 and DeltaG298 of -10.3 kcal/mol. Eight extended variants of T1 (named T2 -T9) were fully characterized and T7 was identified as a suitable candidate for crystallographic studies. We solved the crystal structures of the T1- and T7-NMM complexes at 2.39 and 2.34 A resolution, respectively. Both complexes form a 5'-5' dimer of parallel GQs capped by NMM at the 3' G-quartet, supporting the 1:1 binding stoichiometry. Our work provides invaluable details about GQ-ligand binding interactions and informs the design of novel anticancer drugs that selectively recognize specific GQs and modulate their stability for therapeutic purposes. | |||
Biophysical and X-ray structural studies of the (GGGTT)3GGG G-quadruplex in complex with N-methyl mesoporphyrin IX.,Lin LY, McCarthy S, Powell BM, Manurung Y, Xiang IM, Dean WL, Chaires B, Yatsunyk LA PLoS One. 2020 Nov 18;15(11):e0241513. doi: 10.1371/journal.pone.0241513., eCollection 2020. PMID:33206666<ref>PMID:33206666</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6pnk" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Tetrahymena thermophila]] | |||
[[Category: Lin LY]] | [[Category: Lin LY]] | ||
[[Category: Yatsunyk LA]] | [[Category: Yatsunyk LA]] | ||
Latest revision as of 10:32, 11 October 2023
Crystal structure of the G-quadruplex formed by (GGGTT)3GGG in complex with N-methylmesoporphryin IXCrystal structure of the G-quadruplex formed by (GGGTT)3GGG in complex with N-methylmesoporphryin IX
Structural highlights
Publication Abstract from PubMedThe G-quadruplex (GQ) is a well-studied non-canonical DNA structure formed by G-rich sequences found at telomeres and gene promoters. Biological studies suggest that GQs may play roles in regulating gene expression, DNA replication, and DNA repair. Small molecule ligands were shown to alter GQ structure and stability and thereby serve as novel therapies, particularly against cancer. In this work, we investigate the interaction of a G-rich sequence, 5'-GGGTTGGGTTGGGTTGGG-3' (T1), with a water-soluble porphyrin, N-methyl mesoporphyrin IX (NMM) via biophysical and X-ray crystallographic studies. UV-vis and fluorescence titrations, as well as a Job plot, revealed a 1:1 binding stoichiometry with an impressively tight binding constant of 30-50 muM-1 and DeltaG298 of -10.3 kcal/mol. Eight extended variants of T1 (named T2 -T9) were fully characterized and T7 was identified as a suitable candidate for crystallographic studies. We solved the crystal structures of the T1- and T7-NMM complexes at 2.39 and 2.34 A resolution, respectively. Both complexes form a 5'-5' dimer of parallel GQs capped by NMM at the 3' G-quartet, supporting the 1:1 binding stoichiometry. Our work provides invaluable details about GQ-ligand binding interactions and informs the design of novel anticancer drugs that selectively recognize specific GQs and modulate their stability for therapeutic purposes. Biophysical and X-ray structural studies of the (GGGTT)3GGG G-quadruplex in complex with N-methyl mesoporphyrin IX.,Lin LY, McCarthy S, Powell BM, Manurung Y, Xiang IM, Dean WL, Chaires B, Yatsunyk LA PLoS One. 2020 Nov 18;15(11):e0241513. doi: 10.1371/journal.pone.0241513., eCollection 2020. PMID:33206666[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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