1xa5: Difference between revisions
New page: left|200px<br /><applet load="1xa5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xa5, resolution 2.12Å" /> '''Structure of Calmodu... |
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[[Image:1xa5.gif|left|200px]]<br /><applet load="1xa5" size=" | [[Image:1xa5.gif|left|200px]]<br /><applet load="1xa5" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1xa5, resolution 2.12Å" /> | caption="1xa5, resolution 2.12Å" /> | ||
'''Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid'''<br /> | '''Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid'''<br /> | ||
==Overview== | ==Overview== | ||
3'-(beta-Chloroethyl)-2',4'-dioxo-3,5'-spiro-oxazolidino-4-deacetoxyvinbla | 3'-(beta-Chloroethyl)-2',4'-dioxo-3,5'-spiro-oxazolidino-4-deacetoxyvinbla stine (KAR-2) is a potent anti-microtubular agent that arrests mitosis in cancer cells without significant toxic side effects. In this study we demonstrate that in addition to targeting microtubules, KAR-2 also binds calmodulin, thereby countering the antagonistic effects of trifluoperazine. To determine the basis of both properties of KAR-2, the three-dimensional structure of its complex with Ca(2+)-calmodulin has been characterized both in solution using NMR and when crystallized using x-ray diffraction. Heterocorrelation ((1)H-(15)N heteronuclear single quantum coherence) spectra of (15)N-labeled calmodulin indicate a global conformation change (closure) of the protein upon its binding to KAR-2. The crystal structure at 2.12-A resolution reveals a more complete picture; KAR-2 binds to a novel structure created by amino acid residues of both the N- and C-terminal domains of calmodulin. Although first detected by x-ray diffraction of the crystallized ternary complex, this conformational change is consistent with its solution structure as characterized by NMR spectroscopy. It is noteworthy that a similar tertiary complex forms when calmodulin binds KAR-2 as when it binds trifluoperazine, even though the two ligands contact (for the most part) different amino acid residues. These observations explain the specificity of KAR-2 as an anti-microtubular agent; the drug interacts with a novel drug binding domain on calmodulin. Consequently, KAR-2 does not prevent calmodulin from binding most of its physiological targets. | ||
==About this Structure== | ==About this Structure== | ||
1XA5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with CA and KAR as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1XA5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=KAR:'>KAR</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XA5 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: vinca alkaloid]] | [[Category: vinca alkaloid]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:52:36 2008'' | ||
Revision as of 16:52, 21 February 2008
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Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid
OverviewOverview
3'-(beta-Chloroethyl)-2',4'-dioxo-3,5'-spiro-oxazolidino-4-deacetoxyvinbla stine (KAR-2) is a potent anti-microtubular agent that arrests mitosis in cancer cells without significant toxic side effects. In this study we demonstrate that in addition to targeting microtubules, KAR-2 also binds calmodulin, thereby countering the antagonistic effects of trifluoperazine. To determine the basis of both properties of KAR-2, the three-dimensional structure of its complex with Ca(2+)-calmodulin has been characterized both in solution using NMR and when crystallized using x-ray diffraction. Heterocorrelation ((1)H-(15)N heteronuclear single quantum coherence) spectra of (15)N-labeled calmodulin indicate a global conformation change (closure) of the protein upon its binding to KAR-2. The crystal structure at 2.12-A resolution reveals a more complete picture; KAR-2 binds to a novel structure created by amino acid residues of both the N- and C-terminal domains of calmodulin. Although first detected by x-ray diffraction of the crystallized ternary complex, this conformational change is consistent with its solution structure as characterized by NMR spectroscopy. It is noteworthy that a similar tertiary complex forms when calmodulin binds KAR-2 as when it binds trifluoperazine, even though the two ligands contact (for the most part) different amino acid residues. These observations explain the specificity of KAR-2 as an anti-microtubular agent; the drug interacts with a novel drug binding domain on calmodulin. Consequently, KAR-2 does not prevent calmodulin from binding most of its physiological targets.
About this StructureAbout this Structure
1XA5 is a Single protein structure of sequence from Bos taurus with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
The structure of the complex of calmodulin with KAR-2: a novel mode of binding explains the unique pharmacology of the drug., Horvath I, Harmat V, Perczel A, Palfi V, Nyitray L, Nagy A, Hlavanda E, Naray-Szabo G, Ovadi J, J Biol Chem. 2005 Mar 4;280(9):8266-74. Epub 2004 Dec 13. PMID:15596444
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