1tw2

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[[Image:1tw2.gif|left|200px]]<br /><applet load="1tw2" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1tw2, resolution 2.50&Aring;" />
 
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'''Crystal structure of Carminomycin-4-O-methyltransferase (DnrK) in complex with S-adenosyl-L-homocystein (SAH) and 4-methoxy-e-rhodomycin T (M-ET)'''<br />
 
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==Overview==
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==Crystal structure of Carminomycin-4-O-methyltransferase (DnrK) in complex with S-adenosyl-L-homocystein (SAH) and 4-methoxy-e-rhodomycin T (M-ET)==
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One of the final steps in the biosynthesis of the widely used anti-tumor drug daunorubicin in Streptomyces peucetius is the methylation of the 4-hydroxyl group of the tetracyclic ring system. This reaction is catalyzed by the S-adenosyl-L-methionine-dependent carminomycin 4-O-methyltransferase DnrK. The crystal structure of the ternary complex of this enzyme with the bound products S-adenosyl-L-homocysteine and 4-methoxy-epsilon-rhodomycin T has been determined to a 2.35-angstroms resolution. DnrK is a homodimer, and the subunit displays the typical fold of small molecule O-methyltransferases. The structure provides insights into the recognition of the anthracycline substrate and also suggests conformational changes as part of the catalytic cycle of the enzyme. The position and orientation of the bound ligands are consistent with an SN2 mechanism of methyl transfer. Mutagenesis experiments on a putative catalytic base confirm that DnrK most likely acts as an entropic enzyme in that rate enhancement is mainly due to orientational and proximity effects. This contrasts the mechanism of DnrK with that of other O-methyltransferases where acid/base catalysis has been demonstrated to be an essential contribution to rate enhancement.
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<StructureSection load='1tw2' size='340' side='right'caption='[[1tw2]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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==About this Structure==
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<table><tr><td colspan='2'>[[1tw2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_peucetius Streptomyces peucetius]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TW2 FirstGlance]. <br>
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1TW2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_peucetius Streptomyces peucetius] with <scene name='pdbligand=SAH:'>SAH</scene> and <scene name='pdbligand=ERT:'>ERT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TW2 OCA].
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ERT:METHYL+(4R)-2-ETHYL-2,5,12-TRIHYDROXY-7-METHOXY-6,11-DIOXO-4-{[2,3,6-TRIDEOXY-3-(DIMETHYLAMINO)-BETA-D-RIBO-HEXOPYRANOSYL]OXY}-1H,2H,3H,4H,6H,11H-TETRACENE-1-CARBOXYLATE'>ERT</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
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==Reference==
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1tw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tw2 OCA], [https://pdbe.org/1tw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tw2 RCSB], [https://www.ebi.ac.uk/pdbsum/1tw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tw2 ProSAT]</span></td></tr>
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Crystal structure of a ternary complex of DnrK, a methyltransferase in daunorubicin biosynthesis, with bound products., Jansson A, Koskiniemi H, Mantsala P, Niemi J, Schneider G, J Biol Chem. 2004 Sep 24;279(39):41149-56. Epub 2004 Jul 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15273252 15273252]
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</table>
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[[Category: Single protein]]
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== Function ==
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[https://www.uniprot.org/uniprot/DNRK_STRPE DNRK_STRPE] Involved in the biosynthesis of the anthracyclines carminomycin and daunorubicin (daunomycin) which are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers. In vivo, catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the 4-O-position of carminomycin to form daunorubicin. In vitro, it also methylates the anthracyclines rhodomycin D (10-carbomethoxy-13-deoxycarminomycin) and 13-deoxy-carminomycin at the 4-hydroxyl position. It is quite specific with respect to the length of the carbohydrate chain at the C7 position, but it can accept substrates with bulky substituent at C10 position.<ref>PMID:15273252</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tw/1tw2_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1tw2 ConSurf].
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<div style="clear:both"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Streptomyces peucetius]]
[[Category: Streptomyces peucetius]]
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[[Category: Jansson, A.]]
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[[Category: Jansson A]]
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[[Category: Koskiniemi, H.]]
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[[Category: Koskiniemi H]]
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[[Category: Mantsala, P.]]
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[[Category: Mantsala P]]
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[[Category: Niemi, J.]]
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[[Category: Niemi J]]
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[[Category: SPINE, Structural Proteomics in Europe.]]
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[[Category: Schneider G]]
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[[Category: Schneider, G.]]
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[[Category: ERT]]
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[[Category: SAH]]
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[[Category: anthracycline]]
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[[Category: methylate]]
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[[Category: methyltransferase]]
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[[Category: polyketide]]
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[[Category: s-adenosyl-l-homocystein]]
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[[Category: spine]]
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[[Category: streptomyces]]
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[[Category: structural genomics]]
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[[Category: structural proteomics in europe]]
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[[Category: tailoring enzyme]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:17:58 2008''
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Current revision

Crystal structure of Carminomycin-4-O-methyltransferase (DnrK) in complex with S-adenosyl-L-homocystein (SAH) and 4-methoxy-e-rhodomycin T (M-ET)

PDB ID 1tw2

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