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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-4256 | |||||||||
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Title | Structure of an inhibitor-bound ABC transporter | |||||||||
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Function / homology | ![]() biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / renal urate salt excretion / sphingolipid transporter activity / urate metabolic process / urate transmembrane transporter activity / Abacavir transmembrane transport / organic anion transport ...biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / renal urate salt excretion / sphingolipid transporter activity / urate metabolic process / urate transmembrane transporter activity / Abacavir transmembrane transport / organic anion transport / external side of apical plasma membrane / sphingolipid biosynthetic process / organic anion transmembrane transporter activity / Sphingolipid de novo biosynthesis / xenobiotic transport across blood-brain barrier / export across plasma membrane / ABC-type xenobiotic transporter / Paracetamol ADME / transepithelial transport / Ciprofloxacin ADME / cellular detoxification / ABC-type xenobiotic transporter activity / NFE2L2 regulating MDR associated enzymes / ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Jackson SM / Manolaridis I / Kowal J / Zechner M / Taylor NMI / Bause M / Bauer S / Bartholomaeus R / Stahlberg H / Bernhardt G ...Jackson SM / Manolaridis I / Kowal J / Zechner M / Taylor NMI / Bause M / Bauer S / Bartholomaeus R / Stahlberg H / Bernhardt G / Koenig B / Buschauer A / Altmann KH / Locher KP | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. Authors: Scott M Jackson / Ioannis Manolaridis / Julia Kowal / Melanie Zechner / Nicholas M I Taylor / Manuel Bause / Stefanie Bauer / Ruben Bartholomaeus / Guenther Bernhardt / Burkhard Koenig / ...Authors: Scott 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 / ![]() ![]() ![]() Abstract: 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 ...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. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 10.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13 KB 13 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.4 KB | Display | ![]() |
Images | ![]() | 79.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6ffcMC ![]() 6hijMC ![]() 3953C ![]() 4246C ![]() 6etiC ![]() 6feqC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.812 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Nanodisc-reconstituted ABCG2 in complex with MZ29 inhibitor
Entire | Name: Nanodisc-reconstituted ABCG2 in complex with MZ29 inhibitor |
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Components |
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-Supramolecule #1: Nanodisc-reconstituted ABCG2 in complex with MZ29 inhibitor
Supramolecule | Name: Nanodisc-reconstituted ABCG2 in complex with MZ29 inhibitor type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: ATP-binding cassette sub-family G member 2
Macromolecule | Name: ATP-binding cassette sub-family G member 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 73.395742 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DYKDDDDKGS SSSNVEVFIP VSQGNTNGFP ATASNDLKAF TEGAVLSFHN ICYRVKLKSG FLPCRKPVEK EILSNINGIM KPGLNAILG PTGGGKSSLL DVLAARKDPS GLSGDVLING APRPANFKCN SGYVVQDDVV MGTLTVRENL QFSAALRLAT T MTNHEKNE ...String: DYKDDDDKGS SSSNVEVFIP VSQGNTNGFP ATASNDLKAF TEGAVLSFHN ICYRVKLKSG FLPCRKPVEK EILSNINGIM KPGLNAILG PTGGGKSSLL DVLAARKDPS GLSGDVLING APRPANFKCN SGYVVQDDVV MGTLTVRENL QFSAALRLAT T MTNHEKNE RINRVIQELG LDKVADSKVG TQFIRGVSGG ERKRTSIGME LITDPSILFL DEPTTGLDSS TANAVLLLLK RM SKQGRTI IFSIHQPRYS IFKLFDSLTL LASGRLMFHG PAQEALGYFE SAGYHCEAYN NPADFFLDII NGDSTAVALN REE DFKATE IIEPSKQDKP LIEKLAEIYV NSSFYKETKA ELHQLSGGEK KKKITVFKEI SYTTSFCHQL RWVSKRSFKN LLGN PQASI AQIIVTVVLG LVIGAIYFGL KNDSTGIQNR AGVLFFLTTN QCFSSVSAVE LFVVEKKLFI HEYISGYYRV SSYFL GKLL SDLLPMRMLP SIIFTCIVYF MLGLKPKADA FFVMMFTLMM VAYSASSMAL AIAAGQSVVS VATLLMTICF VFMMIF SGL LVNLTTIASW LSWLQYFSIP RYGFTALQHN EFLGQNFCPG LNATGNNPCN YATCTGEEYL VKQGIDLSPW GLWKNHV AL ACMIVIFLTI AYLKLLFLKK YS |
-Macromolecule #2: ~{tert}-butyl 3-[(2~{S},5~{S},8~{S})-14-cyclopentyloxy-2-(2-methy...
Macromolecule | Name: ~{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 type: ligand / ID: 2 / Number of copies: 2 / Formula: BWQ |
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Molecular weight | Theoretical: 523.664 Da |
Chemical component information | ![]() ChemComp-BWQ: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 0.4 mg/mL |
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Buffer | pH: 7.5 |
Vitrification | Cryogen name: ETHANE-PROPANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Specialist optics | Energy filter - Name: GIF Quantum LS |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 2-50 / Average electron dose: 100.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |