2n96: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 2n96 is ~~ON HOLD~~

==An unexpected mode of small molecule DNA binding provides the structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A==

== Structural highlights ==

<table><tr><td colspan='2'>[[2n96]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N96 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N96 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4JF:(1R,1R,2S,2S,3R,3R,5AR,10AR,11AS)-2-[(2,6-DIDEOXY-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSYL)OXY]-2,2-DIETHYL-11,11-DIHYDRAZINYL-6,6,9,9-TETRAHYDROXY-4,4,5,5,10,10-HEXAOXO-1,1-BIS{[2,4,6-TRIDEOXY-4-(DIMETHYLAMINO)-BETA-L-ARABINO-HEXOPYRANOSYL]OXY}[2,2,3,3,4,4,5,5,5A,8,10,10,10A,11A-TETRADECAHYDRO-1H,1H-[3,3-BIBENZO[B]FLUORENE]]-2-YL+2,6-DIDEOXY-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSIDE'>4JF</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=2n96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n96 OCA], [http://pdbe.org/2n96 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n96 RCSB], [http://www.ebi.ac.uk/pdbsum/2n96 PDBsum]</span></td></tr>

</table>

== Publication Abstract from PubMed ==

(-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C2-symmetric structure that contains two unusual diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC)2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association.

~~Authors:~~ Woo~~, C.M.~~, Li, Z., Paulson~~, E.~~, Herzon, S.B.

Structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A.,Woo CM, Li Z, Paulson EK, Herzon SB Proc Natl Acad Sci U S A. 2016 Feb 29. pii: 201519846. PMID:26929332<ref>PMID:26929332</ref>

~~Description: An unexpected mode~~ of ~~small molecule DNA binding provides~~ the ~~structural basis for DNA cleavage by the potent antiproliferative agent (~~-)-~~lomaiviticin A~~

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased Structures~~]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Herzon, S B]]

[[Category: Li, Z]]

[[Category: Paulson, E]]

[[Category: Woo, C.M]]

[[Category: Woo, C M]]

[[Category: ~~Li, Z~~]]

[[Category: Diazofluorene]]

[[Category: ~~Herzon, S.B~~]]

[[Category: Dna]]

[[Category: Intercalator]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 2n96 is ON HOLD
+==An unexpected mode of small molecule DNA binding provides the structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A==
+<StructureSection load='2n96' size='340' side='right' caption='[[2n96]], [[NMR_Ensembles_of_Models | 6 NMR models]]' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2n96]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N96 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N96 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4JF:(1R,1R,2S,2S,3R,3R,5AR,10AR,11AS)-2-[(2,6-DIDEOXY-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSYL)OXY]-2,2-DIETHYL-11,11-DIHYDRAZINYL-6,6,9,9-TETRAHYDROXY-4,4,5,5,10,10-HEXAOXO-1,1-BIS{[2,4,6-TRIDEOXY-4-(DIMETHYLAMINO)-BETA-L-ARABINO-HEXOPYRANOSYL]OXY}[2,2,3,3,4,4,5,5,5A,8,10,10,10A,11A-TETRADECAHYDRO-1H,1H-[3,3-BIBENZO[B]FLUORENE]]-2-YL+2,6-DIDEOXY-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSIDE'>4JF</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=2n96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n96 OCA], [http://pdbe.org/2n96 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n96 RCSB], [http://www.ebi.ac.uk/pdbsum/2n96 PDBsum]</span></td></tr>
+</table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+(-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C2-symmetric structure that contains two unusual diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC)2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association.
-Authors: Woo, C.M., Li, Z., Paulson, E., Herzon, S.B.
+Structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A.,Woo CM, Li Z, Paulson EK, Herzon SB Proc Natl Acad Sci U S A. 2016 Feb 29. pii: 201519846. PMID:26929332<ref>PMID:26929332</ref>
-Description: An unexpected mode of small molecule DNA binding provides the structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 2n96" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Herzon, S B]]
+[[Category: Li, Z]]
 [[Category: Paulson, E]]
-[[Category: Woo, C.M]]
+[[Category: Woo, C M]]
-[[Category: Li, Z]]
+[[Category: Diazofluorene]]
-[[Category: Herzon, S.B]]
+[[Category: Dna]]
+[[Category: Intercalator]]