View source for 7niv


==Nanodisc reconstituted human ABCB4 in complex with 4B1-Fab and QA2-Fab (phosphatidylcholine-bound, occluded conformation)==
<StructureSection load='7niv' size='340' side='right'caption='[[7niv]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7niv]] is a 5 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=7NIV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NIV 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]] 3.6&#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=DLP:1,2-DILINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>DLP</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=7niv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7niv OCA], [https://pdbe.org/7niv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7niv RCSB], [https://www.ebi.ac.uk/pdbsum/7niv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7niv ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MDR3_HUMAN MDR3_HUMAN] Low phospholipid-associated cholelithiasis;Progressive familial intrahepatic cholestasis type 3;Intrahepatic cholestasis of pregnancy. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/MDR3_HUMAN MDR3_HUMAN] Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts (PubMed:7957936, PubMed:8898203, PubMed:9366571, PubMed:17523162, PubMed:23468132, PubMed:24806754, PubMed:24723470, PubMed:24594635, PubMed:21820390). Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to further enrichment of SM and cholesterol in raft membranes in hepatocytes (PubMed:23468132). Required for proper phospholipid bile formation (By similarity). Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP-dependent manner (PubMed:24045840). Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane (PubMed:9366571, PubMed:28012258). In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts (PubMed:21820390). Does not confer multidrug resistance (By similarity).[UniProtKB:P21440]<ref>PMID:17523162</ref> <ref>PMID:21820390</ref> <ref>PMID:23468132</ref> <ref>PMID:24045840</ref> <ref>PMID:24594635</ref> <ref>PMID:24723470</ref> <ref>PMID:24806754</ref> <ref>PMID:28012258</ref> <ref>PMID:7957936</ref> <ref>PMID:8898203</ref> <ref>PMID:9366571</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
ABCB4 is expressed in hepatocytes and translocates phosphatidylcholine into bile canaliculi. The mechanism of specific lipid recruitment from the canalicular membrane, which is essential to mitigate the cytotoxicity of bile salts, is poorly understood. We present cryogenic electron microscopy structures of human ABCB4 in three distinct functional conformations. An apo-inward structure reveals how phospholipid can be recruited from the inner leaflet of the membrane without flipping its orientation. An occluded structure reveals a single phospholipid molecule in a central cavity. Its choline moiety is stabilized by cation-pi interactions with an essential tryptophan residue, rationalizing the specificity of ABCB4 for phosphatidylcholine. In an inhibitor-bound structure, a posaconazole molecule blocks phospholipids from reaching the central cavity. Using a proteoliposome-based translocation assay with fluorescently labeled phosphatidylcholine analogs, we recapitulated the substrate specificity of ABCB4 in vitro and confirmed the role of the key tryptophan residue. Our results provide a structural basis for understanding an essential translocation step in the generation of bile and its sensitivity to azole drugs.

Structures of ABCB4 provide insight into phosphatidylcholine translocation.,Nosol K, Bang-Sorensen R, Irobalieva RN, Erramilli SK, Stieger B, Kossiakoff AA, Locher KP Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2106702118. doi: , 10.1073/pnas.2106702118. PMID:34385322<ref>PMID:34385322</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7niv" style="background-color:#fffaf0;"></div>

==See Also==
*[[ABC transporter 3D structures|ABC transporter 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Locher KP]]
[[Category: Nosol K]]