6tet: Difference between revisions
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==The structure of CYP121 in complex with inhibitor L21== | ==The structure of CYP121 in complex with inhibitor L21== | ||
<StructureSection load='6tet' size='340' side='right'caption='[[6tet]]' scene=''> | <StructureSection load='6tet' size='340' side='right'caption='[[6tet]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TET FirstGlance]. <br> | <table><tr><td colspan='2'>[[6tet]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TET FirstGlance]. <br> | ||
</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=6tet FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tet OCA], [https://pdbe.org/6tet PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tet RCSB], [https://www.ebi.ac.uk/pdbsum/6tet PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tet ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=N5Z:1-[(~{E})-3-[4-(4-fluorophenyl)phenyl]prop-2-enyl]imidazole'>N5Z</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cyp121, MT2336 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Mycocyclosin_synthase Mycocyclosin synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.19.70 1.14.19.70] </span></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=6tet FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tet OCA], [https://pdbe.org/6tet PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tet RCSB], [https://www.ebi.ac.uk/pdbsum/6tet PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tet ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/CP121_MYCTO CP121_MYCTO]] Catalyzes C-C bond formation between the carbons ortho to the phenolic hydroxyl of cyclo(L-tyr-L-tyr) (cYY) producing mycocyclosin. Can also use cyclo(L-Tyr-L-Phe) (cYF), cyclo(L-Tyr-L-Trp) (cYW) and cyclo(L-Tyr-L-3,4-dihydroxyphenylalanine) (cY-DOPA) as substrate (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
CYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein, we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity toward CYP121, and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesis of promising compounds and led to the identification of favorable features for affinity and/or activity and hit compounds with 2.7-fold improved potency. Mode of action studies show that the hit compounds inhibit substrate conversion and highlighted CYP121 as the main antimycobacterial target of our compounds. Exemplified complex crystal structures of CYP121 with three inhibitors reveal a common binding site. Engaging in both hydrophobic interactions as well as hydrogen bonding to the sixth iron ligand, our compounds block a solvent channel leading to the active site heme. Additionally, we report the first CYP inhibitors that are able to reduce the intracellular replication of M. bovis BCG in macrophages, emphasizing their potential as future drug candidates against TB. | |||
Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.,Walter I, Adam S, Gentilini MV, Kany AM, Brengel C, Thomann A, Sparwasser T, Kohnke J, Hartmann RW ChemMedChem. 2021 Sep 16;16(18):2786-2801. doi: 10.1002/cmdc.202100283. Epub 2021, Jun 22. PMID:34010508<ref>PMID:34010508</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tet" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Adam S]] | [[Category: Mycocyclosin synthase]] | ||
[[Category: Koehnke J]] | [[Category: Adam, S]] | ||
[[Category: Koehnke, J]] | |||
[[Category: Complex]] | |||
[[Category: Cyp121]] | |||
[[Category: Inhibitor]] | |||
[[Category: Oxidoreductase]] | |||