6fn4: Difference between revisions
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<StructureSection load='6fn4' size='340' side='right' caption='[[6fn4]], [[Resolution|resolution]] 4.14Å' scene=''> | <StructureSection load='6fn4' size='340' side='right' caption='[[6fn4]], [[Resolution|resolution]] 4.14Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6fn4]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FN4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6fn4]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FN4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PE:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>3PE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PE:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>3PE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6fn1|6fn1]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6fn1|6fn1]]</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=6fn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fn4 OCA], [http://pdbe.org/6fn4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fn4 RCSB], [http://www.ebi.ac.uk/pdbsum/6fn4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fn4 ProSAT]</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=6fn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fn4 OCA], [http://pdbe.org/6fn4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fn4 RCSB], [http://www.ebi.ac.uk/pdbsum/6fn4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fn4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes. | |||
Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.,Alam A, Kung R, Kowal J, McLeod RA, Tremp N, Broude EV, Roninson IB, Stahlberg H, Locher KP Proc Natl Acad Sci U S A. 2018 Feb 13. pii: 1717044115. doi:, 10.1073/pnas.1717044115. PMID:29440498<ref>PMID:29440498</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6fn4" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Lk3 transgenic mice]] | |||
[[Category: Alam, A]] | [[Category: Alam, A]] | ||
[[Category: Locher, K P]] | [[Category: Locher, K P]] | ||
[[Category: Membrane protein]] | [[Category: Membrane protein]] | ||
[[Category: Membrane transport protein abcb1 abc exporter small molecule inhibitor antibody complex]] | [[Category: Membrane transport protein abcb1 abc exporter small molecule inhibitor antibody complex]] | ||
Revision as of 10:21, 28 February 2018
Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Structural highlights
Publication Abstract from PubMedThe multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes. Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.,Alam A, Kung R, Kowal J, McLeod RA, Tremp N, Broude EV, Roninson IB, Stahlberg H, Locher KP Proc Natl Acad Sci U S A. 2018 Feb 13. pii: 1717044115. doi:, 10.1073/pnas.1717044115. PMID:29440498[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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