6gim

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'''Unreleased structure'''
 
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The entry 6gim is ON HOLD
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==Structure of the DNA duplex d(AAATTT)2 with [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2- yl)amino)benzamide] - (drug JNI18)==
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<StructureSection load='6gim' size='340' side='right' caption='[[6gim]], [[Resolution|resolution]] 1.43&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6gim]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GIM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GIM FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EZK:[4-[(3-chloranyl-4-imidazolidin-2-ylideneazaniumyl-phenyl)carbamoyl]phenyl]-imidazolidin-2-ylidene-azanium'>EZK</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<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=6gim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gim OCA], [http://pdbe.org/6gim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gim RCSB], [http://www.ebi.ac.uk/pdbsum/6gim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gim ProSAT]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Trypanosoma brucei, the causative agent of sleeping sickness (Human African Trypanosomiasis, HAT), contains a kinetoplast with the mitochondrial DNA (kDNA), comprising of &gt;70% AT base pairs. This has prompted studies of drugs interacting with AT-rich DNA, such as the N-phenylbenzamide bis(2-aminoimidazoline) derivatives 1 [4-((4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((4,5-dihydro-1H-imidazol-2-yl)amin o)phenyl)benzamide dihydrochloride] and 2 [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-im idazol-2-yl)amino)benzamide] as potential drugs for HAT. Both compounds show in vitro effects against T. brucei and in vivo curative activity in a mouse model of HAT. The main objective was to identify their cellular target inside the parasite. We were able to demonstrate that the compounds have a clear effect on the S-phase of T. brucei cell cycle by inflicting specific damage on the kinetoplast. Surface plasmon resonance (SPR)-biosensor experiments show that the drug can displace HMG box-containing proteins essential for kDNA function from their kDNA binding sites. The crystal structure of the complex of the oligonucleotide d[AAATTT]2 with compound 1 solved at 1.25 A (PDB-ID: 5LIT) shows that the drug covers the minor groove of DNA, displaces bound water and interacts with neighbouring DNA molecules as a cross-linking agent. We conclude that 1 and 2 are powerful trypanocides that act directly on the kinetoplast, a structure unique to the order Kinetoplastida.
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Authors: Millan, C.R., Dardonvile, C., de Koning, H.P., Saperas, N., Campos, J.L.
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Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast.,Millan CR, Acosta-Reyes FJ, Lagartera L, Ebiloma GU, Lemgruber L, Nue Martinez JJ, Saperas N, Dardonville C, de Koning HP, Campos JL Nucleic Acids Res. 2017 Jun 16. doi: 10.1093/nar/gkx521. PMID:28637278<ref>PMID:28637278</ref>
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Description: Structure of the DNA duplex d(AAATTT)2 with [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2-yl)amino)benzamide] -(drug JNI18)
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: De Koning, H.P]]
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<div class="pdbe-citations 6gim" style="background-color:#fffaf0;"></div>
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[[Category: Saperas, N]]
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== References ==
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[[Category: Millan, C.R]]
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<references/>
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[[Category: Campos, J.L]]
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__TOC__
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</StructureSection>
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[[Category: Campos, J L]]
[[Category: Dardonvile, C]]
[[Category: Dardonvile, C]]
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[[Category: Koning, H P.de]]
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[[Category: Millan, C R]]
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[[Category: Saperas, N]]
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[[Category: Antiparasitic drug]]
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[[Category: At-rich dna]]
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[[Category: Dna]]
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[[Category: Dna binding drug]]
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[[Category: Minor groove binding drug]]
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[[Category: Trypanosoma brucei]]

Revision as of 21:57, 9 August 2018

Structure of the DNA duplex d(AAATTT)2 with [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2- yl)amino)benzamide] - (drug JNI18)

6gim, resolution 1.43Å

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