+
Open data
-
Basic information
Entry | Database: PDB / ID: 6ffc | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Structure of an inhibitor-bound ABC transporter | |||||||||
![]() | ATP-binding cassette sub-family G member 2 | |||||||||
![]() | TRANSPORT PROTEIN / ABC transporter | |||||||||
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 / Sphingolipid de novo biosynthesis / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / transepithelial transport / export across plasma membrane / ABC-type xenobiotic transporter / Paracetamol ADME / Ciprofloxacin ADME / NFE2L2 regulating MDR associated enzymes / ABC-type xenobiotic transporter activity / 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 / brush border membrane / Iron uptake and transport / mitochondrial 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 | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.56 Å | |||||||||
![]() | Jackson, S.M. / Manolaridis, I. / Kowal, J. / Zechner, M. / Taylor, N.M.I. / Bause, M. / Bauer, S. / Bartholomaeus, R. / Stahlberg, H. / Bernhardt, G. ...Jackson, S.M. / Manolaridis, I. / Kowal, J. / Zechner, M. / Taylor, N.M.I. / Bause, M. / Bauer, S. / Bartholomaeus, R. / Stahlberg, H. / Bernhardt, G. / Koenig, B. / Buschauer, A. / Altmann, K.H. / Locher, K.P. | |||||||||
Funding support | ![]()
| |||||||||
![]() | ![]() 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 |
|
-
Structure visualization
Movie |
![]() |
---|---|
Structure viewer | Molecule: ![]() ![]() |
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 201.7 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 166.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 854.5 KB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 862.6 KB | Display | |
Data in XML | ![]() | 41.6 KB | Display | |
Data in CIF | ![]() | 62.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 4256MC ![]() 3953C ![]() 4246C ![]() 6etiC ![]() 6feqC ![]() 6hijC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
#1: Protein | Mass: 73395.742 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Chemical | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component | Name: Nanodisc-reconstituted ABCG2 in complex with MZ29 inhibitor Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
---|---|
Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE-PROPANE |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 100 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
EM imaging optics | Energyfilter name: GIF Quantum LS |
Image scans | Movie frames/image: 50 / Used frames/image: 2-50 |
-
Processing
EM software |
| ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 2098186 | ||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.56 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 402348 / Symmetry type: POINT |