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=='''Structure of Oligonucleotide/Drug complex (1xcs)<ref>PMID: 15926069 </ref>'''==
=='''Structure of Oligonucleotide/Drug Complex (1xcs)<ref>PMID: 15926069 </ref>'''==
by Michael Beauregard, Annie Burton, Jianlong Li, Daniel Marco, and Nathaneal Park
by Michael Beauregard, Annie Burton, Jianlong Li, Daniel Marco, and Nathaneal Park


[[Student Projects for UMass Chemistry 423 Spring 2016]]
[[Student Projects for UMass Chemistry 423 Spring 2016]]
<StructureSection load='1xcs' size='350' side='right' caption='caption for Molecular Playground (PDB entry [[1xcs]])' scene='48/483883/Homecomplex/2'>
<StructureSection load='1xcs' size='350' side='right' caption='This cancer-treating complex is formed by an anthraquinone drug that intercalates into DNA (PDB entry [[1xcs]])' scene='48/483883/Homecomplex/2'>


==Introduction==
==Introduction==
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The 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione complex was studied using synchrotron radiation, which is the energy emitted from particles traveling near the speed of light, which identified ionic sites and areas of high electron density. The binding site of the drug compound is one of these high electron density areas, and was a key component in it's identification. The electron density mappings also provides insight on issues typical with the intercalation of aromatic ligands such as their degrees of freedom and the effect of counterions. The aromatic anthraquinone derivative ligand is disordered disordered in the binding site with two solvable positions which are 180 degree rotations of each other. With respect to the issue of ionic strength, DNA is a polyanion therefore positively charged counterions shielding the interactions between the DNA and the drug is worth noting. In the case of Na+, it has been resolved near the binding site of the drug. In short, this DNA/Anthraquinone derivative complex provides a potential anti-cancer drug and information about the role of positively charged ions in the intercalation of the drug compound.
The 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione complex was studied using synchrotron radiation, which is the energy emitted from particles traveling near the speed of light, which identified ionic sites and areas of high electron density. The binding site of the drug compound is one of these high electron density areas, and was a key component in it's identification. The electron density mappings also provides insight on issues typical with the intercalation of aromatic ligands such as their degrees of freedom and the effect of counterions. The aromatic anthraquinone derivative ligand is disordered disordered in the binding site with two solvable positions which are 180 degree rotations of each other. With respect to the issue of ionic strength, DNA is a polyanion therefore positively charged counterions shielding the interactions between the DNA and the drug is worth noting. In the case of Na+, it has been resolved near the binding site of the drug. In short, this DNA/Anthraquinone derivative complex provides a potential anti-cancer drug and information about the role of positively charged ions in the intercalation of the drug compound.
==Overall Structure==
The intercalation of DNA and drug compounds has been studied thoroughly as a inhibitor of tumorigenesis or pathogenesis which is key in the progression of most cancers. Most intercalated ligands are aromatic compounds that bond between base pairs through non-covalent interactions. In this case the nucleotide d(CGTACG) was complexed with an anthraquinone derivative. This derivative, 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione, provided researchers with the information needed to solve <scene name='48/483883/Rainbow_sheet/1'>the structure of the complex</scene>  using X-Ray crystallography. Along with the structure, the important forces involved in binding were analyzed and described as heavily reliant on cations. Furthermore, the binding site seems to be specific to anthracene and similar molecules. Therefore, the potential for drug compounds to be carried by this nucleotide complex requires further research with respect to binding affinity, solubility, toxicology, and specificity with other analogues.


The 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione complex was studied using synchrotron radiation, which is the energy emitted from particles traveling near the speed of light, which identified ionic sites and areas of high electron density. The binding site of the drug compound is one of these high electron density areas, and was a key component in it's identification. The electron density mappings also provides insight on issues typical with the intercalation of aromatic ligands such as their degrees of freedom and the effect of counterions. The aromatic anthraquinone derivative ligand is disordered disordered in the binding site with two solvable positions which are 180 degree rotations of each other. With respect to the issue of ionic strength, DNA is a polyanion therefore positively charged counterions shielding the interactions between the DNA and the drug is worth noting.
==Overall Structure==
==Overall Structure==


The 1xcs (model at right) complex is a small, simple globular DNA-drug complex, and as such lacks any traditional protein-associated structures such as secondary beta sheets or alpha helices. The complex consists of two complimentary strands of DNA. A simplified model of 1xcs is shown <scene name='48/483883/Title/4'>here,</scene> with the nitrogenous bases removed for clarity. The deoxyribose backbones can be followed from 5' to 3' following along each strand from blue to red. Note that the strands are antiparallel where they are (hydrogen) bonded. <scene name='48/483883/1xcs_with_side_chains/2'>1xcs with its hydrogen bonding regions displayed (black)</scene> visualizes this bonding in the middle region of the complex, again following each strand from blue to red from 5' to 3' ends.
The 1xcs (model at right) complex is a small, simple globular DNA-drug complex, and as such lacks any traditional protein-associated structures such as secondary beta sheets or alpha helices. The complex consists of two complimentary strands of DNA. A simplified model of 1xcs is shown <scene name='48/483883/Title/4'>here,</scene> with the nitrogenous bases removed for clarity. The deoxyribose backbones can be followed from 5' to 3' following along each strand from blue to red. Note that the strands are antiparallel where they are (hydrogen) bonded. <scene name='48/483883/1xcs_with_side_chains/2'>1xcs with its hydrogen bonding regions displayed (black)</scene> visualizes this bonding in the middle region of the complex, again following each strand from blue to red from 5' to 3' ends.


The 1xcs complex also binds to metal ions in more than one location, which have been shown to be important to the drug's binding ability. Different metal ions may be present, including Na(+) and Co(2+). The main metal ions sites are colored pink in <scene name='48/483883/1xcs_with_pink_metal_ions/2'>this</scene> scene. One other metal binding site was noted, which had the ability to bind <scene name='48/483883/Barium_binding_site/1'>Ba(2+)</scene>. This ability to strongly bind metal ions was also important for x-ray crystallographic purposes, as it enabled researchers to form crystals of the complex by relying on interactions between neighboring molecules' binding sites. It is also believed that the tight packing of the 1xcs complex in its solid form contributes to its ability to retain drug molecules (see "Binding Interactions").  
The 1xcs complex also binds to metal ions in more than one location, which have been shown to be important to the drug's binding ability. Different metal ions may be present, including Na(+) and Co(2+). The main metal ions sites are colored pink in <scene name='48/483883/1xcs_with_pink_metal_ions/2'>this</scene> scene. One other metal binding site was noted, which had the ability to bind <scene name='48/483883/Barium_binding_site/1'>Ba(2+)</scene> (teal). This ability to strongly bind metal ions was also important for x-ray crystallographic purposes, as it enabled researchers to form crystals of the complex by relying on interactions between neighboring molecules' binding sites. It is also believed that the tight packing of the 1xcs complex in its solid form contributes to its ability to retain drug molecules (see "Binding Interactions").  


==Binding Interactions==
==Binding Interactions==
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==Quiz Question 1==
==Quiz Question 1==
A unique site is the __ ion found associated with the <scene name='48/483883/O6_atom_of_two_guanines/1'>O6_atom_of_two_guanines</scene>, which gives additional strength to the guanine–Co2+–guanine interaction. A Mg2+ B Co2+ C Ba2+ D Mg2+
This complex serves to interrupt two enzymes involved in cell replication: Taq polymerase and <scene name='48/483883/This_complex/1'>this enzyme</scene>.
  A. nuclease
  B. telomerase
  C. ligase
  D. topoisomerase


==See Also==
==See Also==

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