2k4l - Revision history

OCA at 06:44, 1 May 2024

2024-05-01T06:44:05Z

←Older revision		Revision as of 06:44, 1 May 2024
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	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [https://pdbe.org/2k4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [https://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l 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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [https://pdbe.org/2k4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [https://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l ProSAT]</span></td></tr>
	</table>		</table>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	The naturally occurring pyrrolo[2,1- c][1,4]benzodiazepine (PBD) monomers such as sibiromycin, anthramycin, and tomaymycin form stable covalent adducts with duplex DNA at purine-guanine-purine sites. A correlative relationship between DNA-binding affinity, as measured by enhanced thermal denaturation temperature of calf thymus DNA ( T m), and cytotoxicity is well documented for these naturally occurring compounds and a range of synthetic analogues with sibiromycin having the highest Delta T m value (16.3 degrees C), reflecting favorable hydrogen-bonding interactions between the molecule and DNA bases. We report here that, surprisingly, the structurally simple synthetic C2-(2-naphthyl)-substituted pyrrolo[2,1- c][1,4]benzodiazepine monomer ( 5) has a Delta T m value (15.8 degrees C) similar to that of sibiromycin and significantly higher than the values for either anthramycin (13.0 degrees C) or tomaymycin (2.6 degrees C). 5 also has similar cytotoxic potency to sibiromycin which is widely regarded as the most potent naturally occurring PBD monomer. To investigate this, we have used NMR in conjunction with molecular dynamics to study the 2:1 adduct formed between 5 and the DNA duplex d(AATCTTTAAAGATT) 2. In contrast to the hydrogen-bonding interactions which predominate in the case of sibiromycin and anthramycin adducts, we have shown that the high binding affinity of 5 is due predominantly to hydrophobic (van der Waals) interactions. The high-resolution 2D NOESY, TOCSY, and COSY data obtained have also allowed unequivocal determination of the orientation of the PBD molecule (A-ring toward 3'-end of covalently bound strand), the stereochemistry at the C11 position of the PBD (C11 S), and the conformation of the C2-naphthyl ring which extends along the floor of the minor groove thus optimizing hydrophobic interactions with DNA. These results provide opportunities for future drug design in terms of extending planar hydrophobic groups at the C2 position of PBDs to maximize binding affinity.
-
-	Solution Structure of a 2:1 C2-(2-Naphthyl) Pyrrolo[2,1-c][1,4]benzodiazepine DNA Adduct: Molecular Basis for Unexpectedly High DNA Helix Stabilization.,Antonow D, Barata T, Jenkins TC, Parkinson GN, Howard PW, Thurston DE, Zloh M Biochemistry. 2008 Oct 17. PMID:18925745<ref>PMID:18925745</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 2k4l" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 13:36, 30 August 2023

2023-08-30T13:36:15Z

←Older revision		Revision as of 13:36, 30 August 2023
Line 1:		Line 1:

	==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==		==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==
-	<StructureSection load='2k4l' size='340' side='right'caption='[[2k4l~~]], [[NMR_Ensembles_of_Models \| 10 NMR models~~]]' scene=''>	+	<StructureSection load='2k4l' size='340' side='right'caption='[[2k4l]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K4L FirstGlance]. <br>		<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K4L FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [https://pdbe.org/2k4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [https://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l 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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [https://pdbe.org/2k4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [https://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l ProSAT]</span></td></tr>
	</table>		</table>
Line 21:		Line 22:
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Antonow, D]]	+	[[Category: Antonow D]]
-	[[Category: Barata, T]]	+	[[Category: Barata T]]
-	[[Category: Howard~~, P W~~]]	+	[[Category: Howard PW]]
-	[[Category: Jenkins~~, T C~~]]	+	[[Category: Jenkins TC]]
-	[[Category: Parkinson~~, G N~~]]	+	[[Category: Parkinson GN]]
-	[[Category: Thurston~~, D E~~]]	+	[[Category: Thurston DE]]
-	[[Category: Zloh, M]]	+	[[Category: Zloh M]]
-	~~[[Category: Dna]]~~	+
-	~~[[Category: Dna adduct]]~~	+
-	~~[[Category: Pbd~~]]	+

OCA at 13:28, 24 November 2021

2021-11-24T13:28:26Z

←Older revision		Revision as of 13:28, 24 November 2021
Line 3:		Line 3:
	<StructureSection load='2k4l' size='340' side='right'caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>		<StructureSection load='2k4l' size='340' side='right'caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2K4L FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K4L FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [~~http~~://pdbe.org/2k4l PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l 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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [https://pdbe.org/2k4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [https://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">

OCA at 06:54, 19 February 2020

2020-02-19T06:54:38Z

←Older revision		Revision as of 06:54, 19 February 2020
Line 1:		Line 1:

	==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==		==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==
-	<StructureSection load='2k4l' size='340' side='right' caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>	+	<StructureSection load='2k4l' size='340' side='right'caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>		<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>
Line 20:		Line 20:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Antonow, D]]		[[Category: Antonow, D]]
	[[Category: Barata, T]]		[[Category: Barata, T]]

OCA at 11:07, 18 July 2018

2018-07-18T11:07:14Z

←Older revision		Revision as of 11:07, 18 July 2018
Line 1:		Line 1:
		+
	==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==		==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==
	<StructureSection load='2k4l' size='340' side='right' caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>		<StructureSection load='2k4l' size='340' side='right' caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>
Line 4:		Line 5:
	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>		<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [http://pdbe.org/2k4l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [http://www.ebi.ac.uk/pdbsum/2k4l PDBsum]</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [http://pdbe.org/2k4l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [http://www.ebi.ac.uk/pdbsum/2k4l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4l ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">

OCA at 18:06, 10 September 2015

2015-09-10T18:06:05Z

←Older revision		Revision as of 18:06, 10 September 2015
Line 4:		Line 4:
	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>		<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [http://www.ebi.ac.uk/pdbsum/2k4l PDBsum]</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [http://pdbe.org/2k4l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [http://www.ebi.ac.uk/pdbsum/2k4l PDBsum]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 14:		Line 14:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 2k4l" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 10:39, 25 January 2015

2015-01-25T10:39:20Z

←Older revision		Revision as of 10:39, 25 January 2015
Line 18:		Line 18:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Antonow, D.]]	+	[[Category: Antonow, D]]
-	[[Category: Barata, T.]]	+	[[Category: Barata, T]]
-	[[Category: Howard, P W.]]	+	[[Category: Howard, P W]]
-	[[Category: Jenkins, T C.]]	+	[[Category: Jenkins, T C]]
-	[[Category: Parkinson, G N.]]	+	[[Category: Parkinson, G N]]
-	[[Category: Thurston, D E.]]	+	[[Category: Thurston, D E]]
-	[[Category: Zloh, M.]]	+	[[Category: Zloh, M]]
	[[Category: Dna]]		[[Category: Dna]]
	[[Category: Dna adduct]]		[[Category: Dna adduct]]
	[[Category: Pbd]]		[[Category: Pbd]]

OCA at 09:26, 5 November 2014

2014-11-05T09:26:49Z

←Older revision		Revision as of 09:26, 5 November 2014
Line 1:		Line 1:
-	[[~~Image~~:2k4l.~~png~~\|~~left\|200px~~]]	+	==Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.==
		+	<StructureSection load='2k4l' size='340' side='right' caption='[[2k4l]], [[NMR_Ensembles_of_Models \| 10 NMR models]]' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[2k4l]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K4L FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PZD:(11AS)-7,8-DIMETHOXY-2-NAPHTHALEN-2-YL-1,10,11,11A-TETRAHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPIN-5-ONE'>PZD</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=2k4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2k4l RCSB], [http://www.ebi.ac.uk/pdbsum/2k4l PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The naturally occurring pyrrolo[2,1- c][1,4]benzodiazepine (PBD) monomers such as sibiromycin, anthramycin, and tomaymycin form stable covalent adducts with duplex DNA at purine-guanine-purine sites. A correlative relationship between DNA-binding affinity, as measured by enhanced thermal denaturation temperature of calf thymus DNA ( T m), and cytotoxicity is well documented for these naturally occurring compounds and a range of synthetic analogues with sibiromycin having the highest Delta T m value (16.3 degrees C), reflecting favorable hydrogen-bonding interactions between the molecule and DNA bases. We report here that, surprisingly, the structurally simple synthetic C2-(2-naphthyl)-substituted pyrrolo[2,1- c][1,4]benzodiazepine monomer ( 5) has a Delta T m value (15.8 degrees C) similar to that of sibiromycin and significantly higher than the values for either anthramycin (13.0 degrees C) or tomaymycin (2.6 degrees C). 5 also has similar cytotoxic potency to sibiromycin which is widely regarded as the most potent naturally occurring PBD monomer. To investigate this, we have used NMR in conjunction with molecular dynamics to study the 2:1 adduct formed between 5 and the DNA duplex d(AATCTTTAAAGATT) 2. In contrast to the hydrogen-bonding interactions which predominate in the case of sibiromycin and anthramycin adducts, we have shown that the high binding affinity of 5 is due predominantly to hydrophobic (van der Waals) interactions. The high-resolution 2D NOESY, TOCSY, and COSY data obtained have also allowed unequivocal determination of the orientation of the PBD molecule (A-ring toward 3'-end of covalently bound strand), the stereochemistry at the C11 position of the PBD (C11 S), and the conformation of the C2-naphthyl ring which extends along the floor of the minor groove thus optimizing hydrophobic interactions with DNA. These results provide opportunities for future drug design in terms of extending planar hydrophobic groups at the C2 position of PBDs to maximize binding affinity.

-	~~{{STRUCTURE_2k4l\| PDB=2k4l \| SCENE= }}~~	+	Solution Structure of a 2:1 C2-(2-Naphthyl) Pyrrolo[2,1-c][1,4]benzodiazepine DNA Adduct: Molecular Basis for Unexpectedly High DNA Helix Stabilization.,Antonow D, Barata T, Jenkins TC, Parkinson GN, Howard PW, Thurston DE, Zloh M Biochemistry. 2008 Oct 17. PMID:18925745<ref>PMID:18925745</ref>

-	~~===Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2~~,~~1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_18925745}}~~	+	== References ==
-		+	<references/>
-	~~==About this Structure==~~	+	__TOC__
-	~~[[2k4l]] is~~ a ~~2 chain structure~~. ~~Full experimental information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=2K4L OCA].~~	+	</StructureSection>
-		+
-	==~~Reference~~==	+
-	<~~ref group="xtra">PMID:018925745<~~/~~ref~~><~~ref group="xtra">PMID:017397227</ref><references group="xtra"~~/>	+
	[[Category: Antonow, D.]]		[[Category: Antonow, D.]]
	[[Category: Barata, T.]]		[[Category: Barata, T.]]

OCA at 13:10, 30 January 2013

2013-01-30T13:10:24Z

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	[[Image:2k4l.png\|left\|200px]]		[[Image:2k4l.png\|left\|200px]]

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	{{STRUCTURE_2k4l\| PDB=2k4l \| SCENE= }}		{{STRUCTURE_2k4l\| PDB=2k4l \| SCENE= }}

	===Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.===		===Solution structure of a 2:1C2-(2-naphthyl)pyrrolo[2,1-c][1,4]benzodiazepine (PBD) DNA adduct: molecular basis for unexpectedly high DNA helix stabilization.===

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	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~18925745~~</ref><ref group="xtra">PMID:~~17397227~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:018925745</ref><ref group="xtra">PMID:017397227</ref><references group="xtra"/>
	[[Category: Antonow, D.]]		[[Category: Antonow, D.]]
	[[Category: Barata, T.]]		[[Category: Barata, T.]]

OCA: Protected "2k4l" [edit=sysop:move=sysop]

2011-03-14T22:38:10Z

Protected "2k4l" [edit=sysop:move=sysop]

←Older revision

Revision as of 22:38, 14 March 2011