6t0j
From Proteopedia
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==Crystal structure of CYP124 in complex with SQ109== | ==Crystal structure of CYP124 in complex with SQ109== | ||
| - | <StructureSection load='6t0j' size='340' side='right'caption='[[6t0j]]' scene=''> | + | <StructureSection load='6t0j' size='340' side='right'caption='[[6t0j]], [[Resolution|resolution]] 1.25Å' 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=6T0J OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6t0j]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T0J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T0J FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.25Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=RWZ:N-[(2Z)-3,7-DIMETHYLOCTA-2,6-DIEN-1-YL]-N-[(1R,3S,5R,7R)-TRICYCLO[3.3.1.1~3,7~]DEC-2-YL]ETHANE-1,2-DIAMINE'>RWZ</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=6t0j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t0j OCA], [https://pdbe.org/6t0j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t0j RCSB], [https://www.ebi.ac.uk/pdbsum/6t0j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t0j ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CP124_MYCTU CP124_MYCTU] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Spreading of the multidrug-resistant (MDR) strains of the one of the most harmful pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 A-resolution crystal structure of the CYP124-SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the omega-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs. | ||
| + | |||
| + | Hydroxylation of Antitubercular Drug Candidate, SQ109, by Mycobacterial Cytochrome P450.,Bukhdruker S, Varaksa T, Grabovec I, Marin E, Shabunya P, Kadukova M, Grudinin S, Kavaleuski A, Gusach A, Gilep A, Borshchevskiy V, Strushkevich N Int J Mol Sci. 2020 Oct 16;21(20). pii: ijms21207683. doi: 10.3390/ijms21207683. PMID:33081390<ref>PMID:33081390</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6t0j" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: Borshchevskiy V]] | [[Category: Borshchevskiy V]] | ||
[[Category: Bukhdruker S]] | [[Category: Bukhdruker S]] | ||
Current revision
Crystal structure of CYP124 in complex with SQ109
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