This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

316d

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Current revision

Selectivity of F8-actinomycin D for RNA:DNA hybrids and its anti-leukemia activity

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/316d"

@@ Line 1: / Line 1: @@
-[[Image:316d.gif|left|200px]]<br /><applet load="316d" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="316d, resolution 3.000&Aring;" />
-'''SELECTIVITY OF F8-ACTINOMYCIN D FOR RNA:DNA HYBRIDS AND ITS ANTI-LEUKEMIA ACTIVITY'''<br />
-==Overview==
+==Selectivity of F8-actinomycin D for RNA:DNA hybrids and its anti-leukemia activity==
-Although many compounds have been found that bind to DNA in various ways, and exhibit various biological activities, few compounds that specifically, bind to RNA or RNA:DNA hybrids are known, even though such compounds are, expected to have important biological properties. For example, one, characteristic function of the retroviruses, which is generally not found, in eukaryotic cells, is the production of an RNA:DNA hybrid in the viral, replication phase. If an agent is designed to bind only to an RNA:DNA, hybrid, and not to DNA or to RNA, such an agent might be able to inhibit, specifically the RNase H activity of retroviral reverse transcriptase, and, therefore suppress viral replication. Actinomycin D is known to bind to, double-stranded DNA, but not to RNA, because steric hindrance between the, 2-amino group of the phenoxazone ring and the 2'-hydroxyl group of RNA, prevents intercalation of the compound. However, if the &gt; C-H moiety at, the 8-position of the phenoxazone ring is replaced by a &gt; C-F, a possible, hydrogen-bond acceptor, this analogue (8-fluoro-actinomycin D, F8AMD), might be able to bind intercalatively to an RNA:DNA hybrid by forming an, additional hydrogen bond between F8 and the 2'-hydroxyl group of the, guanosine ribose. To test this hypothesis, the crystal structure of, d(GAAGCTTC)2-F8AMD has been determined at 3.0 A resolution. Based on this, crystal structure, a model in which F8AMD binds into the hybrid, r(GAAGCUUC):d(GAAGCTTC) has been built using molecular mechanics and, dynamic methods. These structural studies indicate that F8AMD binds, intercalatively to a B-form double-stranded DNA whereas the drug, intercalates into an RNA:DNA hybrid taking an A-form conformation. In the, RNA:DNA hybrid complex, the F8 atom is located so as to be able to, interact to an O2' hydroxyl group with either an O-H...F hydrogen bond or, H+...F- electrostatic interaction. This interaction might stabilize the, F8AMD molecule in the RNA:DNA hybrid. A binding study indicates that both, actinomycin D (AMD) and F8AMD bind intercalatively not only to, double-stranded DNAs, but also to RNA:DNA hybrids. Although the overall, binding capacity of F8AMD (k = 4.5 x 10(5) M-1) is reduced slightly in, comparison with AMD itself (k = 1.8 x 10(6) M-1), F8AMD tends to bind, relatively more favorably than AMD to the RNA:DNA hybrids. The drugs', effects on RNA synthesis in HeLa cells indicates that the binding, capacities of AMD and F8AMD correlates strongly to their RNA synthesis, inhibitory activities. F8AMD required a concentration of 78 nM to inhibit, RNA polymerase activity in HeLa cells by 50%, whereas AMD reached the same, inhibitory level at 30 nM. Surprisingly, F8AMD exhibits unique selectivity, against leukemia cells as does another C8-derivatized AMD analogue, N8AMD., F8AMD inhibits 50% of leukemia cell growth at less than 1.0 nM whereas 10-, to 130-fold-higher drug concentrations are required to inhibit the growth, of other tumor cell lines by 50%. The GI50 value of F8AMD for leukemia, cells is the lowest among the GI50 values for all other AMD derivatives, tested. By contrast, AMD is quite potent and kills most cells at less than, 50 nM concentration, but it does not show any selectivity for certain cell, lines. This indicates that AMD should have very limited use as an, antitumor agent. It is difficult to rationalize why F8AMD and N8AMD show, such strong selectivity against leukemia cells. However, this study and, our previous study (J. Am. Chem. Soc. 1994, 116, 7971) indicated that, F8AMD and N8AMD tended to bind more favorably to RNA:DNA hybrids. Thus, the unique antileukemia selectivity shown by F8AMD and N8AMD might be used, by the agents binding to RNA:DNA hybrids rather than to double-stranded, DNA.
+<StructureSection load='316d' size='340' side='right'caption='[[316d]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+== Structural highlights ==
-==About this Structure==
+<table><tr><td colspan='2'>[[316d]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_antibioticus Streptomyces antibioticus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=316D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=316D FirstGlance]. <br>
-D is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=PXF:'>PXF</scene>, <scene name='pdbligand=SAR:'>SAR</scene>, <scene name='pdbligand=MVA:'>MVA</scene>, <scene name='pdbligand=DTH:'>DTH</scene>, <scene name='pdbligand=DVA:'>DVA</scene> and <scene name='pdbligand=DPR:'>DPR</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=316D OCA].
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DVA:D-VALINE'>DVA</scene>, <scene name='pdbligand=MVA:N-METHYLVALINE'>MVA</scene>, <scene name='pdbligand=PXF:2-AMINO-1,9-DICARBONYL-4,6-DIMETHYL-10-DEHYDRO-8-FLUORO-3-OXOPHENOXAZINE'>PXF</scene>, <scene name='pdbligand=SAR:SARCOSINE'>SAR</scene></td></tr>
-==Reference==
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=316d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=316d OCA], [https://pdbe.org/316d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=316d RCSB], [https://www.ebi.ac.uk/pdbsum/316d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=316d ProSAT]</span></td></tr>
-Selectivity of F8-actinomycin D for RNA:DNA hybrids and its anti-leukemia activity., Takusagawa F, Takusagawa KT, Carlson RG, Weaver RF, Bioorg Med Chem. 1997 Jun;5(6):1197-207. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9222513 9222513]
+</table>
-[[Category: Protein complex]]
+__TOC__
-[[Category: Carlson, R.G.]]
+</StructureSection>
-[[Category: Takusagawa, F.]]
+[[Category: Large Structures]]
-[[Category: Takusagawa, K.T.]]
+[[Category: Streptomyces antibioticus]]
-[[Category: Weaver, R.F.]]
+[[Category: Carlson RG]]
-[[Category: DPR]]
+[[Category: Takusagawa F]]
-[[Category: DTH]]
+[[Category: Takusagawa KT]]
-[[Category: DVA]]
+[[Category: Weaver RF]]
-[[Category: MVA]]
-[[Category: PXF]]
-[[Category: SAR]]
-[[Category: complexed with drug]]
-[[Category: double helix]]
-[[Category: right handed dna]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jan 29 21:34:59 2008''

316d

From Proteopedia

Current revision

Selectivity of F8-actinomycin D for RNA:DNA hybrids and its anti-leukemia activity

Structural highlights

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox