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Structure paper

TitleStructural basis of small-molecule inhibition of human multidrug transporter ABCG2.
Journal, issue, pagesNat Struct Mol Biol, Vol. 25, Issue 4, Page 333-340, Year 2018
Publish dateApr 2, 2018
AuthorsScott M Jackson / Ioannis Manolaridis / Julia Kowal / Melanie Zechner / Nicholas M I Taylor / Manuel Bause / Stefanie Bauer / Ruben Bartholomaeus / Guenther Bernhardt / Burkhard Koenig / Armin Buschauer / Henning Stahlberg / Karl-Heinz Altmann / Kaspar P Locher /
PubMed AbstractABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors ...ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the transmembrane domains (TMDs). Extensive chemical modifications of the Ko143 scaffold combined with in vitro functional analyses revealed the details of ABCG2 interactions with this compound family and provide a basis for the design of novel inhibitors and modulators.
External linksNat Struct Mol Biol / PubMed:29610494
MethodsEM (single particle)
Resolution3.1 - 3.6 Å
Structure data

3953

6eti

EMDB-3953, PDB-6eti:
Structure of inhibitor-bound ABCG2
Method: EM (single particle) / Resolution: 3.1 Å

4246

6feq

EMDB-4246, PDB-6feq:
Structure of inhibitor-bound ABCG2
Method: EM (single particle) / Resolution: 3.6 Å

4256

6ffc

6hij

EMDB-4256, PDB-6ffc:
Structure of an inhibitor-bound ABC transporter
PDB-6hij: Cryo-EM structure of the human ABCG2-MZ29-Fab complex with cholesterol and PE lipids docked
Method: EM (single particle) / Resolution: 3.56 Å

Chemicals

ChemComp-BWQ:
~{tert}-butyl 3-[(2~{S},5~{S},8~{S})-14-cyclopentyloxy-2-(2-methylpropyl)-4,7-bis(oxidanylidene)-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraen-5-yl]propanoate

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

ChemComp-D6T:
~{N}-[5-[1-[4-[2-[6-methoxy-7-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-3,4-dihydro-1~{H}-isoquinolin-2-yl]ethyl]phenyl]-1,2,3-triazol-4-yl]-2-propanoyl-phenyl]quinoline-2-carboxamide

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM / Discrete optimized protein energy

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Multidrug transporter / ABCG2 / MZ29 / inhibitor / MB136 / TRANSPORT PROTEIN / ABC transporter

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