View source for 8iz7


==cryo-EM structure of sulindac-bound hMRP4==
<StructureSection load='8iz7' size='340' side='right'caption='[[8iz7]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8iz7]] 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=8IZ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IZ7 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]] 3.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SUZ:[(1Z)-5-FLUORO-2-METHYL-1-{4-[METHYLSULFINYL]BENZYLIDENE}-1H-INDEN-3-YL]ACETIC+ACID'>SUZ</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=8iz7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8iz7 OCA], [https://pdbe.org/8iz7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8iz7 RCSB], [https://www.ebi.ac.uk/pdbsum/8iz7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8iz7 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 ==
Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.

Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4.,Huang Y, Xue C, Wang L, Bu R, Mu J, Wang Y, Liu Z Commun Biol. 2023 May 22;6(1):549. doi: 10.1038/s42003-023-04935-7. PMID:37217525<ref>PMID:37217525</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8iz7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Huang Y]]
[[Category: Liu ZM]]