View source for 9gcx


==Crystal structure of bovine Cytochrome bc1 in complex with inhibitor F8==
<StructureSection load='9gcx' size='340' side='right'caption='[[9gcx]], [[Resolution|resolution]] 3.52&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9gcx]] is a 11 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9GCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GCX FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.522&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IKG:2-methyl-3-[4-[4-(trifluoromethyloxy)phenoxy]phenyl]-3,5,7,8-tetrahydropyrano[4,3-b]pyridin-4-one'>A1IKG</scene>, <scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=LOP:(1R)-2-{[(R)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(DODECANOYLOXY)METHYL]ETHYL+(9Z)-OCTADEC-9-ENOATE'>LOP</scene>, <scene name='pdbligand=PSC:(7R,17E,20E)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSA-17,20-DIEN-1-AMINIUM+4-OXIDE'>PSC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9gcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9gcx OCA], [https://pdbe.org/9gcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9gcx RCSB], [https://www.ebi.ac.uk/pdbsum/9gcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9gcx ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/QCR1_BOVIN QCR1_BOVIN] This is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between cytochromes c and c1.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aryl quinolone derivatives can target the cytochrome bc(1) complex of Plasmodium falciparum, exhibiting excellent in vitro and in vivo antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce pi-pi stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, F14, exhibited significant enhancements in both aqueous solubility (20 muM) and lipophilicity (LogD 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of P. falciparum (IC(50) = 235 nM). The pharmacokinetic studies reported, provide preliminary insights into the in vivo distribution and elimination of F14, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and in silico docking simulations provide insight into the potential mode of action within the cytochrome bc(1) complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of in vivo efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.

Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties.,Ge S, Jian R, Xuan Q, Zhu Y, Ren X, Li W, Chen X, Huang RK, Lee CS, Leung SC, Basilico N, Parapini S, Taramelli D, Pinthong N, Antonyuk SV, O'Neill PM, Sheng Z, Hong WD Eur J Med Chem. 2025 Feb 15;284:117228. doi: 10.1016/j.ejmech.2024.117228. Epub , 2024 Dec 28. PMID:39752821<ref>PMID:39752821</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9gcx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Large Structures]]
[[Category: Antonyuk SV]]
[[Category: Hong W]]
[[Category: ONeill PW]]
[[Category: Pinthong N]]