6tet: Difference between revisions
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<StructureSection load='6tet' size='340' side='right'caption='[[6tet]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='6tet' size='340' side='right'caption='[[6tet]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6tet]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[6tet]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. 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='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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4998689Å</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='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> | <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 == | == Function == | ||
[https://www.uniprot.org/uniprot/CP121_MYCTU CP121_MYCTU] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6tet" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6tet" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Adam | [[Category: Adam S]] | ||
[[Category: Koehnke | [[Category: Koehnke J]] | ||
Latest revision as of 16:00, 24 January 2024
The structure of CYP121 in complex with inhibitor L21The structure of CYP121 in complex with inhibitor L21
Structural highlights
FunctionPublication Abstract from PubMedCYP121 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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