View source for 8xom


==Cryo-EM structure of human ABCC4 in complex with ANP-bound in NBD1 and METHOTREXATE==
<StructureSection load='8xom' size='340' side='right'caption='[[8xom]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8xom]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8XOM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XOM 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]] 3.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=DU0:2-[2-[(1~{S},2~{S},4~{S},5~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5,7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2-oxane]-16-yl]oxyethyl]propane-1,3-diol'>DU0</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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=8xom FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xom OCA], [https://pdbe.org/8xom PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xom RCSB], [https://www.ebi.ac.uk/pdbsum/8xom PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xom ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MRP4_HUMAN MRP4_HUMAN] ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12523936, PubMed:12835412, PubMed:12883481, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12523936, PubMed:12883481, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:17344354, PubMed:18300232). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685).<ref>PMID:11106685</ref> <ref>PMID:11856762</ref> <ref>PMID:12105214</ref> <ref>PMID:12523936</ref> <ref>PMID:12835412</ref> <ref>PMID:12883481</ref> <ref>PMID:15364914</ref> <ref>PMID:15454390</ref> <ref>PMID:16282361</ref> <ref>PMID:17344354</ref> <ref>PMID:17959747</ref> <ref>PMID:18300232</ref> <ref>PMID:26721430</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co-bound in the inward-open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP-bound NBD2-induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with anticancer therapy.

The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport.,Zhu Y, Xing X, Wang F, Chen L, Zhong C, Lu X, Yu Z, Yang Y, Yao Y, Song Q, Han S, Liu Z, Zhang P FEBS Lett. 2024 Jun 17. doi: 10.1002/1873-3468.14955. PMID:38886124<ref>PMID:38886124</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8xom" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Liu Z]]
[[Category: Zhang PF]]