6s7p

From Proteopedia

(Difference between revisions)

Revision as of 12:15, 1 January 2020

Nucleotide bound ABCB4

Structural highlights

6s7p is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	ABCB4, MDR3, PGY3 (HUMAN)
Activity:	P-type phospholipid transporter, with EC number 7.6.2.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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

[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]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

Publication Abstract from PubMed

ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 A. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg(2+). The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.

Structure of the human lipid exporter ABCB4 in a lipid environment.,Olsen JA, Alam A, Kowal J, Stieger B, Locher KP Nat Struct Mol Biol. 2019 Dec 23. pii: 10.1038/s41594-019-0354-3. doi:, 10.1038/s41594-019-0354-3. PMID:31873305^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Morita SY, Kobayashi A, Takanezawa Y, Kioka N, Handa T, Arai H, Matsuo M, Ueda K. Bile salt-dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4. Hepatology. 2007 Jul;46(1):188-99. doi: 10.1002/hep.21591. PMID:17523162 doi:http://dx.doi.org/10.1002/hep.21591
↑ Groen A, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, Williamson C, Seppen J, Van den Oever K, Mok KS, Paulusma CC, Linton KJ, Oude Elferink RP. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology. 2011 Nov;141(5):1927-37.e1-4. doi:, 10.1053/j.gastro.2011.07.042. Epub 2011 Aug 4. PMID:21820390 doi:http://dx.doi.org/10.1053/j.gastro.2011.07.042
↑ Morita SY, Tsuda T, Horikami M, Teraoka R, Kitagawa S, Terada T. Bile salt-stimulated phospholipid efflux mediated by ABCB4 localized in nonraft membranes. J Lipid Res. 2013 May;54(5):1221-30. doi: 10.1194/jlr.M032425. Epub 2013 Mar 6. PMID:23468132 doi:http://dx.doi.org/10.1194/jlr.M032425
↑ Degiorgio D, Corsetto PA, Rizzo AM, Colombo C, Seia M, Costantino L, Montorfano G, Tomaiuolo R, Bordo D, Sansanelli S, Li M, Tavian D, Rastaldi MP, Coviello DA. Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction. Eur J Hum Genet. 2014 May;22(5):633-9. doi: 10.1038/ejhg.2013.214. Epub 2013 Sep , 18. PMID:24045840 doi:http://dx.doi.org/10.1038/ejhg.2013.214
↑ Gordo-Gilart R, Andueza S, Hierro L, Martinez-Fernandez P, D'Agostino D, Jara P, Alvarez L. Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut. 2015 Jan;64(1):147-55. doi: 10.1136/gutjnl-2014-306896. Epub 2014 Mar 4. PMID:24594635 doi:http://dx.doi.org/10.1136/gutjnl-2014-306896
↑ Gautherot J, Delautier D, Maubert MA, Ait-Slimane T, Bolbach G, Delaunay JL, Durand-Schneider AM, Firrincieli D, Barbu V, Chignard N, Housset C, Maurice M, Falguieres T. Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations. Hepatology. 2014 Aug;60(2):610-21. doi: 10.1002/hep.27170. Epub 2014 May 19. PMID:24723470 doi:http://dx.doi.org/10.1002/hep.27170
↑ Andress EJ, Nicolaou M, Romero MR, Naik S, Dixon PH, Williamson C, Linton KJ. Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Hepatology. 2014 May;59(5):1921-31. doi: 10.1002/hep.26970. Epub 2014 Apr 1. PMID:24806754 doi:http://dx.doi.org/10.1002/hep.26970
↑ Delaunay JL, Bruneau A, Hoffmann B, Durand-Schneider AM, Barbu V, Jacquemin E, Maurice M, Housset C, Callebaut I, Ait-Slimane T. Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). Hepatology. 2017 Feb;65(2):560-570. doi: 10.1002/hep.28929. Epub 2016 Dec 24. PMID:28012258 doi:http://dx.doi.org/10.1002/hep.28929
↑ Smith AJ, Timmermans-Hereijgers JL, Roelofsen B, Wirtz KW, van Blitterswijk WJ, Smit JJ, Schinkel AH, Borst P. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett. 1994 Nov 14;354(3):263-6. doi: 10.1016/0014-5793(94)01135-4. PMID:7957936 doi:http://dx.doi.org/10.1016/0014-5793(94)01135-4
↑ van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, van Meer G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 1996 Nov 1;87(3):507-17. doi: 10.1016/s0092-8674(00)81370-7. PMID:8898203 doi:http://dx.doi.org/10.1016/s0092-8674(00)81370-7
↑ Crawford AR, Smith AJ, Hatch VC, Oude Elferink RP, Borst P, Crawford JM. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy. J Clin Invest. 1997 Nov 15;100(10):2562-7. doi: 10.1172/JCI119799. PMID:9366571 doi:http://dx.doi.org/10.1172/JCI119799
↑ Olsen JA, Alam A, Kowal J, Stieger B, Locher KP. Structure of the human lipid exporter ABCB4 in a lipid environment. Nat Struct Mol Biol. 2019 Dec 23. pii: 10.1038/s41594-019-0354-3. doi:, 10.1038/s41594-019-0354-3. PMID:31873305 doi:http://dx.doi.org/10.1038/s41594-019-0354-3

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6s7p"

@@ Line 3: / Line 3: @@
 <StructureSection load='6s7p' size='340' side='right'caption='[[6s7p]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6s7p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S7P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S7P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6s7p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S7P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S7P FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ABCB4, MDR3, PGY3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/P-type_phospholipid_transporter P-type phospholipid transporter], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=7.6.2.1 7.6.2.1] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6s7p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s7p OCA], [http://pdbe.org/6s7p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s7p RCSB], [http://www.ebi.ac.uk/pdbsum/6s7p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s7p ProSAT]</span></td></tr>
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://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 an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 A. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg(2+). The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.
+Structure of the human lipid exporter ABCB4 in a lipid environment.,Olsen JA, Alam A, Kowal J, Stieger B, Locher KP Nat Struct Mol Biol. 2019 Dec 23. pii: 10.1038/s41594-019-0354-3. doi:, 10.1038/s41594-019-0354-3. PMID:31873305<ref>PMID:31873305</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6s7p" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: P-type phospholipid transporter]]

6s7p

From Proteopedia

Revision as of 12:15, 1 January 2020

Nucleotide bound ABCB4

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox