6gim
From Proteopedia
(Difference between revisions)
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- | '''Unreleased structure''' | ||
- | + | ==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)== | |
+ | <StructureSection load='6gim' size='340' side='right' caption='[[6gim]], [[Resolution|resolution]] 1.43Å' scene=''> | ||
+ | == Structural highlights == | ||
+ | <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> | ||
+ | </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> | ||
+ | <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> | ||
+ | </table> | ||
+ | <div style="background-color:#fffaf0;"> | ||
+ | == Publication Abstract from PubMed == | ||
+ | Trypanosoma brucei, the causative agent of sleeping sickness (Human African Trypanosomiasis, HAT), contains a kinetoplast with the mitochondrial DNA (kDNA), comprising of >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. | ||
- | + | 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> | |
- | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
- | + | </div> | |
- | + | <div class="pdbe-citations 6gim" style="background-color:#fffaf0;"></div> | |
- | + | == References == | |
- | + | <references/> | |
- | [[Category: Campos, J | + | __TOC__ |
+ | </StructureSection> | ||
+ | [[Category: Campos, J L]] | ||
[[Category: Dardonvile, C]] | [[Category: Dardonvile, C]] | ||
+ | [[Category: Koning, H P.de]] | ||
+ | [[Category: Millan, C R]] | ||
+ | [[Category: Saperas, N]] | ||
+ | [[Category: Antiparasitic drug]] | ||
+ | [[Category: At-rich dna]] | ||
+ | [[Category: Dna]] | ||
+ | [[Category: Dna binding drug]] | ||
+ | [[Category: Minor groove binding drug]] | ||
+ | [[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)
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