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TitleABCG2 transports anticancer drugs via a closed-to-open switch.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 2264, Year 2020
Publish dateMay 8, 2020
AuthorsBenjamin J Orlando / Maofu Liao /
PubMed AbstractABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent structural insights, no anticancer ...ABCG2 is an ABC transporter that extrudes a variety of compounds from cells, and presents an obstacle in treating chemotherapy-resistant cancers. Despite recent structural insights, no anticancer drug bound to ABCG2 has been resolved, and the mechanisms of multidrug transport remain obscure. Such a gap of knowledge limits the development of novel compounds that block or evade this critical molecular pump. Here we present single-particle cryo-EM studies of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics. Without the binding of conformation-selective antibody fragments or inhibitors, the resting ABCG2 adopts a closed conformation. Our cryo-EM, biochemical, and functional analyses reveal the binding mode of three chemotherapeutic compounds, demonstrate how these molecules open the closed conformation of the transporter, and establish that imatinib is particularly effective in stabilizing the inward facing conformation of ABCG2. Together these studies reveal the previously unrecognized conformational cycle of ABCG2.
External linksNat Commun / PubMed:32385283 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 4.1 Å
Structure data

21436

6vxf

EMDB-21436, PDB-6vxf:
Structure of apo-closed ABCG2
Method: EM (single particle) / Resolution: 3.5 Å

21437

6vxh

EMDB-21437, PDB-6vxh:
Structure of ABCG2 bound to imatinib
Method: EM (single particle) / Resolution: 4.0 Å

21438

6vxi

EMDB-21438, PDB-6vxi:
Structure of ABCG2 bound to mitoxantrone
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-21439:
Closed conformation of ABCG2 in the presence of mitoxantrone
Method: EM (single particle) / Resolution: 3.6 Å

21440

6vxj

EMDB-21440, PDB-6vxj:
Structure of ABCG2 bound to SN38
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-21441:
ABCG2 in the apo-closed conformation in the presence of SN38
Method: EM (single particle) / Resolution: 4.0 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-STI:
4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / medication, inhibitor*YM / Imatinib

ChemComp-MIX:
1,4-DIHYDROXY-5,8-BIS({2-[(2-HYDROXYETHYL)AMINO]ETHYL}AMINO)-9,10-ANTHRACENEDIONE / antineoplastic*YM / Mitoxantrone

ChemComp-RS4:
7-ethyl-10-hydroxycamptothecin / antineoplastic, inhibitor*YM / SN-38

Source
  • homo sapiens (human)
KeywordsTRANSLOCASE / ABCG2 / BCRP / nanodisc / ABC transporter / TRANSLOCASE/TRANSLOCASE INHIBITOR / imatinib / TRANSLOCASE-TRANSLOCASE INHIBITOR complex / mitoxantrone / SN38

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