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Structure paper

TitleStructure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 115, Issue 9, Page E1973-E1982, Year 2018
Publish dateFeb 27, 2018
AuthorsAmer Alam / Raphael Küng / Julia Kowal / Robert A McLeod / Nina Tremp / Eugenia V Broude / Igor B Roninson / Henning Stahlberg / Kaspar P Locher /
PubMed AbstractThe 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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:29440498 / PubMed Central
MethodsEM (single particle)
Resolution3.58 - 6.25 Å
Structure data

4281

6fn1

EMDB-4281, PDB-6fn1:
Zosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Method: EM (single particle) / Resolution: 3.58 Å

4282

6fn4

EMDB-4282, PDB-6fn4:
Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Method: EM (single particle) / Resolution: 4.14 Å

EMDB-4283:
Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) - Map 2 (kinked TM4 and TM10)
Method: EM (single particle) / Resolution: 4.47 Å

EMDB-4284:
Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM). Map3 (straight conformation of TM4 and TM10)
Method: EM (single particle) / Resolution: 4.55 Å

EMDB-4285:
Amphipol reconstituted UIC2 Fab complex of double EQ mutant of human-mouse chimeric ABCB1 (ABCB1HMEQ)
Method: EM (single particle) / Resolution: 6.25 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ZQU:
Zosuquidar / antineoplastic*YM / Zosuquidar

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM / Phosphatidylethanolamine

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Membrane Transport Protein ABCB1 ABC Exporter Small molecule inhibitor Antibody complex

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