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Structure paper

TitleStructural insights into binding-site access and ligand recognition by human ABCB1.
Journal, issue, pagesEMBO J, Vol. 44, Issue 4, Page 991-991006, Year 2025
Publish dateJan 13, 2025
AuthorsDevanshu Kurre / Phuoc X Dang / Le T M Le / Varun V Gadkari / Amer Alam /
PubMed AbstractABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates ...ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution, in the absence of stabilizing antibodies or mutations. The substrate-binding site is located within one half of the molecule and, in the apo state, is obstructed by the transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major TM rearrangements and their ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Furthermore, our data identify secondary structure-breaking residues that impart localized TM flexibility and asymmetry between the two transmembrane domains. The resulting structural changes and lipid interactions that are induced by substrate and inhibitor binding can predict substrate-binding profiles and may direct ABCB1 inhibitor design.
External linksEMBO J / PubMed:39806099 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 4.7 Å
Structure data

45854

9cr8

EMDB-45854, PDB-9cr8:
SapNP reconstituted human ABCB1
Method: EM (single particle) / Resolution: 3.8 Å

45903

9ctc

EMDB-45903, PDB-9ctc:
SapNP reconstituted Human ABCB1 in complex with Zosuquidar and ATP/Mg
Method: EM (single particle) / Resolution: 3.6 Å

45904

9ctf

EMDB-45904, PDB-9ctf:
SapNP Reconstituted Human ABCB1 bound to Taxol in presence of ATP
Method: EM (single particle) / Resolution: 3.9 Å

45906

9ctg

EMDB-45906, PDB-9ctg:
SapNP Reconstituted Human ABCB1 bound to ATP gammaS
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-45931: HUMAN ABCB1 in SapNPs in complex with Taxol
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-45932: HUMAN ABCB1 in SapNPs in complex with Zosuquidar
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-UPL:
UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-ZQU:
Zosuquidar / antineoplastic*YM

ChemComp-TA1:
TAXOL / medication, chemotherapy*YM

ChemComp-MG:
Unknown entry

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / TRANSLOCASE / ABCB1 / P-gp / apo form / nanoparticle / saposin A / MDR1 / p-glycoprotein / pgp / inhibitor bound / saposin / zosuquidar bound / substrate bound / taxol bound / php / ATPgammaS bound / non-hydrolysable nucleotide

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