View source for 8qcm


==ABCG2 in complex with MZ82 and 5D3 Fab==
<StructureSection load='8qcm' size='340' side='right'caption='[[8qcm]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8qcm]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8QCM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QCM FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.39&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=V0U:(2~{S},5~{S},8~{S})-14-methoxy-2-(2-methylpropyl)-5-(phenylmethyl)-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraene-4,7-dione'>V0U</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=8qcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qcm OCA], [https://pdbe.org/8qcm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qcm RCSB], [https://www.ebi.ac.uk/pdbsum/8qcm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qcm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ABCG2_HUMAN ABCG2_HUMAN] High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.<ref>PMID:12958161</ref> <ref>PMID:20705604</ref> <ref>PMID:22132962</ref> <ref>PMID:23189181</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their in vitro modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved in vivo stability.

Modulation of ABCG2 Transporter Activity by Ko143 Derivatives.,Yu Q, Dehghani-Ghahnaviyeh S, Rasouli A, Sadurni A, Kowal J, Bang-Soerensen R, Wen PC, Tinzl-Zechner M, Irobalieva RN, Ni D, Stahlberg H, Altmann KH, Tajkhorshid E, Locher KP ACS Chem Biol. 2024 Oct 24. doi: 10.1021/acschembio.4c00353. PMID:39445888<ref>PMID:39445888</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8qcm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Altmann KH]]
[[Category: Kowal J]]
[[Category: Locher KP]]
[[Category: Ni D]]
[[Category: Stahlberg H]]
[[Category: Tajkhorshid E]]
[[Category: Yu Q]]