+Open data
-Basic information
Entry | Database: PDB / ID: 6vxi | ||||||
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Title | Structure of ABCG2 bound to mitoxantrone | ||||||
Components | Broad substrate specificity ATP-binding cassette transporter ABCG2 | ||||||
Keywords | TRANSLOCASE / ABCG2 / ABC transporter / mitoxantrone | ||||||
Function / homology | Function and homology information biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / sphingolipid transporter activity / external side of apical plasma membrane / renal urate salt excretion / urate transmembrane transporter activity / Abacavir transmembrane transport / urate metabolic process ...biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / sphingolipid transporter activity / external side of apical plasma membrane / renal urate salt excretion / urate transmembrane transporter activity / Abacavir transmembrane transport / urate metabolic process / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / organic anion transport / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / transepithelial transport / export across plasma membrane / ABC-type xenobiotic transporter / Paracetamol ADME / ABC-type xenobiotic transporter activity / Ciprofloxacin ADME / NFE2L2 regulating MDR associated enzymes / Differentiation of keratinocytes in interfollicular epidermis in mammalian skin / cellular detoxification / Heme biosynthesis / Heme degradation / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / Iron uptake and transport / mitochondrial membrane / brush border membrane / transmembrane transport / apical plasma membrane / membrane raft / protein homodimerization activity / ATP hydrolysis activity / nucleoplasm / ATP binding / identical protein binding / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å | ||||||
Authors | Orlando, B.J. / Liao, M. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Commun / Year: 2020 Title: ABCG2 transports anticancer drugs via a closed-to-open switch. Authors: Benjamin J Orlando / Maofu Liao / Abstract: 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 ...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. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6vxi.cif.gz | 199.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6vxi.ent.gz | 166.5 KB | Display | PDB format |
PDBx/mmJSON format | 6vxi.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6vxi_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 6vxi_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 6vxi_validation.xml.gz | 40 KB | Display | |
Data in CIF | 6vxi_validation.cif.gz | 60 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/vx/6vxi ftp://data.pdbj.org/pub/pdb/validation_reports/vx/6vxi | HTTPS FTP |
-Related structure data
Related structure data | 21438MC 6vxfC 6vxhC 6vxjC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 72385.852 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG2, ABCP, BCRP, BCRP1, MXR / Cell line (production host): HEK293F / Production host: Homo sapiens (human) References: UniProt: Q9UNQ0, ABC-type xenobiotic transporter #2: Chemical | #3: Chemical | ChemComp-MIX / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: ABCG2 reconstituted in lipid nanodisc / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | |||||||||||||||
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Molecular weight | Experimental value: NO | |||||||||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||
Source (recombinant) | Organism: Homo sapiens (human) / Cell: HEK293F | |||||||||||||||
Buffer solution | pH: 8 | |||||||||||||||
Buffer component |
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Specimen | Conc.: 1.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||
Specimen support | Details: unspecified / Grid type: Quantifoil R1.2/1.3 | |||||||||||||||
Vitrification | Instrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 92 % |
-Electron microscopy imaging
Experimental equipment | Model: Tecnai Polara / Image courtesy: FEI Company |
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Microscopy | Model: FEI POLARA 300 |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Calibrated magnification: 31000 X / Cs: 2 mm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Average exposure time: 8 sec. / Electron dose: 52 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
Image scans | Movie frames/image: 40 |
-Processing
Software | Name: PHENIX / Version: 1.14_3260: / Classification: refinement | ||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||
3D reconstruction | Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101081 / Symmetry type: POINT | ||||||||||||||||||||
Atomic model building | Space: REAL |