1xa5: Difference between revisions
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'''Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid''' | '''Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid''' | ||
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[[Category: Naray-Szabo, G.]] | [[Category: Naray-Szabo, G.]] | ||
[[Category: Ovadi, J.]] | [[Category: Ovadi, J.]] | ||
[[Category: | [[Category: Calmodulin]] | ||
[[Category: | [[Category: Drug binding]] | ||
[[Category: | [[Category: Kar-2]] | ||
[[Category: | [[Category: Vinca alkaloid]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:46:08 2008'' | |||
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Revision as of 14:46, 3 May 2008
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. 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 Page seeded by OCA on Sat May 3 14:46:08 2008