View source for 1xa5


==Structure of Calmodulin in complex with KAR-2, a bis-indol alkaloid==
<StructureSection load='1xa5' size='340' side='right'caption='[[1xa5]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1xa5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XA5 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=KAR:3+-(BETA-CHLOROETHYL)-2+,4+-DIOXO-3,+5+-SPIRO-OXAZOLIDINO-4-DEACETOXY-VINBLASTINE'>KAR</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1xa5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xa5 OCA], [https://pdbe.org/1xa5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xa5 RCSB], [https://www.ebi.ac.uk/pdbsum/1xa5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xa5 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CALM_BOVIN CALM_BOVIN] Calmodulin mediates the control of a large number of enzymes, ion channels and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases. Together with CEP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (By similarity).
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xa/1xa5_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1xa5 ConSurf].
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== Publication Abstract from PubMed ==
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 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<ref>PMID:15596444</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Calmodulin 3D structures|Calmodulin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Large Structures]]
[[Category: Harmat V]]
[[Category: Hlavanda E]]
[[Category: Horvath I]]
[[Category: Naray-Szabo G]]
[[Category: Ovadi J]]