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| | <StructureSection load='6clx' size='340' side='right'caption='[[6clx]], [[Resolution|resolution]] 2.73Å' scene=''> | | <StructureSection load='6clx' size='340' side='right'caption='[[6clx]], [[Resolution|resolution]] 2.73Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6clx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Streptomyces_sp._cb03234 Streptomyces sp. cb03234]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CLX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CLX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6clx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptomyces_sp._CB03234 Streptomyces sp. CB03234]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CLX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CLX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.73Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">tnmH, AMK26_31990 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1703937 Streptomyces sp. CB03234])</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=6clx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6clx OCA], [https://pdbe.org/6clx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6clx RCSB], [https://www.ebi.ac.uk/pdbsum/6clx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6clx ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6clx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6clx OCA], [http://pdbe.org/6clx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6clx RCSB], [http://www.ebi.ac.uk/pdbsum/6clx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6clx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/A0A125SA05_9ACTN A0A125SA05_9ACTN] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Streptomyces sp. cb03234]] | + | [[Category: Streptomyces sp. CB03234]] |
| - | [[Category: Adhikari, A]] | + | [[Category: Adhikari A]] |
| - | [[Category: Annaval, T]] | + | [[Category: Annaval T]] |
| - | [[Category: Chang, C Y]] | + | [[Category: Chang CY]] |
| - | [[Category: Shen, B]] | + | [[Category: Shen B]] |
| - | [[Category: Yan, X]] | + | [[Category: Yan X]] |
| - | [[Category: Biosynthetic protein]]
| + | |
| - | [[Category: Methyltransferase]]
| + | |
| Structural highlights
Function
A0A125SA05_9ACTN
Publication Abstract from PubMed
The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy.
Characterization of TnmH as an O-Methyltransferase Revealing Insights into Tiancimycin Biosynthesis and Enabling a Biocatalytic Strategy To Prepare Antibody-Tiancimycin Conjugates.,Adhikari A, Teijaro CN, Yan X, Chang CY, Gui C, Liu YC, Crnovcic I, Yang D, Annaval T, Rader C, Shen B J Med Chem. 2020 Aug 13;63(15):8432-8441. doi: 10.1021/acs.jmedchem.0c00799. Epub, 2020 Jul 24. PMID:32658465[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Adhikari A, Teijaro CN, Yan X, Chang CY, Gui C, Liu YC, Crnovcic I, Yang D, Annaval T, Rader C, Shen B. Characterization of TnmH as an O-Methyltransferase Revealing Insights into Tiancimycin Biosynthesis and Enabling a Biocatalytic Strategy To Prepare Antibody-Tiancimycin Conjugates. J Med Chem. 2020 Aug 13;63(15):8432-8441. doi: 10.1021/acs.jmedchem.0c00799. Epub, 2020 Jul 24. PMID:32658465 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00799
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