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| - | [[Image:1xa5.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1xa5| PDB=1xa5 | SCENE= }} | | {{STRUCTURE_1xa5| PDB=1xa5 | SCENE= }} |
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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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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15596444}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15596444 is the PubMed ID number. |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Kar-2]] | | [[Category: Kar-2]] |
| | [[Category: Vinca alkaloid]] | | [[Category: Vinca alkaloid]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:46:08 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 00:09:09 2008'' |
Revision as of 21:09, 28 July 2008
Template:STRUCTURE 1xa5
Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid
Template:ABSTRACT PUBMED 15596444
About this Structure
1XA5 is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
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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