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| | ==NMR structure of a new G-quadruplex forming sequence within the KRAS proto-oncogene promoter region== | | ==NMR structure of a new G-quadruplex forming sequence within the KRAS proto-oncogene promoter region== |
| - | <StructureSection load='5i2v' size='340' side='right'caption='[[5i2v]], [[NMR_Ensembles_of_Models | 11 NMR models]]' scene=''> | + | <StructureSection load='5i2v' size='340' side='right'caption='[[5i2v]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5i2v]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I2V OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5I2V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5i2v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I2V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I2V FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5i2v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i2v OCA], [http://pdbe.org/5i2v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i2v RCSB], [http://www.ebi.ac.uk/pdbsum/5i2v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i2v ProSAT]</span></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=5i2v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i2v OCA], [https://pdbe.org/5i2v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i2v RCSB], [https://www.ebi.ac.uk/pdbsum/5i2v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i2v ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kerkour, A]] | + | [[Category: Kerkour A]] |
| - | [[Category: Mergny, J L]] | + | [[Category: Mergny J-L]] |
| - | [[Category: Salgado, G F]] | + | [[Category: Salgado GF]] |
| - | [[Category: Cancer target]]
| + | |
| - | [[Category: Dna]]
| + | |
| - | [[Category: G-quadruplex]]
| + | |
| - | [[Category: Kra]]
| + | |
| - | [[Category: Proto-oncogene]]
| + | |
| Structural highlights
Publication Abstract from PubMed
Non-canonical base pairing within guanine-rich DNA and RNA sequences can produce G-quartets, whose stacking leads to the formation of a G-quadruplex (G4). G4s can coexist with canonical duplex DNA in the human genome and have been suggested to suppress gene transcription, and much attention has therefore focused on studying G4s in promotor regions of disease-related genes. For example, the human KRAS proto-oncogene contains a nuclease-hypersensitive element (1) located upstream of the major transcription start site. The KRAS NHE region contains a G-rich element within (22RT: 5'-AGGGCGGTGTGGGAATAGGGAA-3') and also encompasses a Myc-associated zinc-finger (MAZ)-binding site that regulates KRAS transcription. The NEH region therefore has been proposed as a target for new drugs that control KRAS transcription, requiring detailed knowledge of the NHE structure. In this study, we report a high-resolution NMR structure of the G-rich element within the KRAS NHE. We found that the G-rich element forms a parallel structure with three G-quartets connected by a four-nucleotide loop and two short one-nucleotide double-chain-reversal loops. In addition, a thymine bulge is found between G8 and G9. The loops of different lengths and the presence of a bulge between the G-quartets are structural elements that potentially can be targeted by small chemical ligands that would further stabilize the structure and interfere or block transcriptional regulators such as MAZ from accessing their binding sites on the KRAS promoter. In conclusion, our work suggests a possible new route for the development of anticancer agents that could supress KRAS expression.
High-resolution 3D NMR structure of the KRAS proto-oncogene promoter reveals key features of a G-quadruplex involved in transcriptional regulation.,Kerkour A, Marquevielle J, Ivashchenko S, Yatsunyk LA, Mergny JL, Salgado GF J Biol Chem. 2017 Mar 22. pii: jbc.M117.781906. doi: 10.1074/jbc.M117.781906. PMID:28330874[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kerkour A, Marquevielle J, Ivashchenko S, Yatsunyk LA, Mergny JL, Salgado GF. High-resolution 3D NMR structure of the KRAS proto-oncogene promoter reveals key features of a G-quadruplex involved in transcriptional regulation. J Biol Chem. 2017 Mar 22. pii: jbc.M117.781906. doi: 10.1074/jbc.M117.781906. PMID:28330874 doi:http://dx.doi.org/10.1074/jbc.M117.781906
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