View source for 9krk


==Cryo-EM structure of human ABCC4 (Apo state)==
<StructureSection load='9krk' size='340' side='right'caption='[[9krk]], [[Resolution|resolution]] 3.29&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9krk]] 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=9KRK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KRK 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]] 3.29&#8491;</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=9krk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9krk OCA], [https://pdbe.org/9krk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9krk RCSB], [https://www.ebi.ac.uk/pdbsum/9krk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9krk 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 ==
BACKGROUND: ABCC4 (ATP-binding cassette sub-family C member 4) is a transporter protein that is primarily localized to the plasma membrane, and its efflux activity is associated with the progression of various cancers and the development of drug resistance. Cyclic adenosine monophosphate (cAMP) is an important biomolecule that is considered a transport substrate of ABCC4. However, there is currently no direct structural understanding of how ABCC4 binds cAMP, and the mechanisms by which it recognizes a diverse range of substrate ligands remain poorly understood. Some studies have indicated that, under physiological conditions, cAMP does not significantly stimulate the ATPase activity of ABCC4, making the commonly used ATPase activity assays for ABC proteins unsuitable for studying cAMP. RESULTS: Here, we successfully resolved the cryo-electron microscopy (cryo-EM) structure of the human ABCC4-cAMP (hABCC4-cAMP) complex, revealing how hABCC4 binds to cAMP and identifying the key residues involved. This structure was compared with two other hABCC4 complex structures we obtained (Methotrexate and Prostaglandin E(2)) and with previously published structures. We discovered some new structural insights into how hABCC4 binds ligands. On the basis of the structural information obtained, we confirmed the feasibility of using 8-[Fluo]-cAMP in a transport assay to detect cAMP translocation and found that some challenges remain to be addressed. CONCLUSIONS: These results suggest that hABCC4 can bind cAMP and exhibits varying degrees of flexibility when binding with different substrates, including cAMP. These findings expand our understanding of the structural biology of ABCC4.

Structural basis of human ABCC4 recognition of cAMP and ligand recognition flexibility.,Wen X, Si K, Zhu D, Zhang A, Guo C, Li M, Tian W Cell Biosci. 2025 Mar 27;15(1):39. doi: 10.1186/s13578-025-01377-y. PMID:40148998<ref>PMID:40148998</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9krk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Li MH]]
[[Category: Wen XP]]