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7les

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<StructureSection load='7les' size='340' side='right'caption='[[7les]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
<StructureSection load='7les' size='340' side='right'caption='[[7les]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7les]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LES FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7les]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Acanthamoeba_castellanii_str._Neff Acanthamoeba castellanii str. Neff]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LES FirstGlance]. <br>
</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=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
</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=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=7les FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7les OCA], [https://pdbe.org/7les PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7les RCSB], [https://www.ebi.ac.uk/pdbsum/7les PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7les 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=7les FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7les OCA], [https://pdbe.org/7les PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7les RCSB], [https://www.ebi.ac.uk/pdbsum/7les PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7les ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[[https://www.uniprot.org/uniprot/L8GJB3_ACACA L8GJB3_ACACA]]
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Acanthamoeba castellanii is a free-living amoeba that can cause severe eye and brain infections in humans. At present, there is no uniformly effective treatment for any of these infections. However, sterol 14alpha-demethylases (CYP51s), heme-containing cytochrome P450 enzymes, are known to be validated drug targets in pathogenic fungi and protozoa. The catalytically active P450 form of CYP51 from A. castellanii (AcCYP51) is stabilized against conversion to the inactive P420 form by dimerization. In contrast, Naegleria fowleri CYP51 (NfCYP51) is monomeric in its active P450 and inactive P420 forms. For these two CYP51 enzymes, we have investigated the interplay between the enzyme activity and oligomerization state using steady-state and time-resolved UV-visible absorption spectroscopy. In both enzymes, the P450 --&gt; P420 transition is favored under reducing conditions. The transition is accelerated at higher pH, which excludes a protonated thiol as the proximal ligand in P420. Displacement of the proximal thiolate ligand is also promoted by adding exogenous nitrogenous ligands (N-ligands) such as imidazole, isavuconazole, and clotrimazole that bind at the opposite, distal heme side. In AcCYP51, the P450 --&gt; P420 transition is faster in the monomer than in the dimer, indicating that the dimeric assembly is critical for stabilizing thiolate coordination to the heme and thus for sustaining AcCYP51 activity. The spectroscopic experiments were complemented with size-exclusion chromatography and X-ray crystallography studies. Collectively, our results indicate that effective inactivation of the AcCYP51 function by azole drugs is due to synergistic interference with AcCYP51 dimerization and promoting irreversible displacement of the proximal heme-thiolate ligand.
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Homodimerization Counteracts the Detrimental Effect of Nitrogenous Heme Ligands on the Enzymatic Activity of Acanthamoeba castellanii CYP51.,Nienhaus K, Sharma V, Nienhaus GU, Podust LM Biochemistry. 2022 Jul 5;61(13):1363-1377. doi: 10.1021/acs.biochem.2c00198. Epub, 2022 Jun 22. PMID:35730528<ref>PMID:35730528</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7les" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Acanthamoeba castellanii str. Neff]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Podust, L M]]
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[[Category: Podust LM]]
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[[Category: Sharma, V]]
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[[Category: Sharma V]]
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[[Category: 14-alpha-demethylase]]
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[[Category: Acanthamoeba]]
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[[Category: Cyp51]]
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[[Category: Ergosterol biosynthesis]]
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[[Category: Oxidoreductase]]
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Revision as of 05:22, 8 September 2022

Acanthamoeba castellanii CYP51 (AcCYP51)-Imidazole complex

PDB ID 7les

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