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Structure paper

TitleStructures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 4376, Year 2021
Publish dateJul 19, 2021
AuthorsQin Yu / Dongchun Ni / Julia Kowal / Ioannis Manolaridis / Scott M Jackson / Henning Stahlberg / Kaspar P Locher /
PubMed AbstractABCG2 is a multidrug transporter that affects drug pharmacokinetics and contributes to multidrug resistance of cancer cells. In previously reported structures, the reaction cycle was halted by the ...ABCG2 is a multidrug transporter that affects drug pharmacokinetics and contributes to multidrug resistance of cancer cells. In previously reported structures, the reaction cycle was halted by the absence of substrates or ATP, mutation of catalytic residues, or the presence of small-molecule inhibitors or inhibitory antibodies. Here we present cryo-EM structures of ABCG2 under turnover conditions containing either the endogenous substrate estrone-3-sulfate or the exogenous substrate topotecan. We find two distinct conformational states in which both the transport substrates and ATP are bound. Whereas the state turnover-1 features more widely separated NBDs and an accessible substrate cavity between the TMDs, turnover-2 features semi-closed NBDs and an almost fully occluded substrate cavity. Substrate size appears to control which turnover state is mainly populated. The conformational changes between turnover-1 and turnover-2 states reveal how ATP binding is linked to the closing of the cytoplasmic side of the TMDs. The transition from turnover-1 to turnover-2 is the likely bottleneck or rate-limiting step of the reaction cycle, where the discrimination of substrates and inhibitors occurs.
External linksNat Commun / PubMed:34282134 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.4 Å
Structure data

12939

7oj8

EMDB-12939, PDB-7oj8:
ABCG2 E1S turnover-2 state
Method: EM (single particle) / Resolution: 3.4 Å

12951

7ojh

EMDB-12951, PDB-7ojh:
ABCG2 topotecan turnover-1 state
Method: EM (single particle) / Resolution: 3.1 Å

12952

7oji

EMDB-12952, PDB-7oji:
ABCG2 topotecan turnover-2 state
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

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

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-FY5:
estrone 3-sulfate / medication, hormone*YM / Estrone sulfate

ChemComp-TTC:
(S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-DIHYDROXY-1H-PYRANO[3',4':6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE / medication, inhibitor*YM / Topotecan

ChemComp-PLC:
DIUNDECYL PHOSPHATIDYL CHOLINE / phospholipid*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / ABC transporter plasma membrane ATP multidrug resistance

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