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- PDB-6ffc: Structure of an inhibitor-bound ABC transporter -

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Basic information

Entry
Database: PDB / ID: 6ffc
TitleStructure of an inhibitor-bound ABC transporter
ComponentsATP-binding cassette sub-family G member 2
KeywordsTRANSPORT PROTEIN / ABC transporter
Function / homology
Function and homology information


biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / renal urate salt excretion / urate metabolic process / urate transmembrane transporter activity / Abacavir transmembrane transport / organic anion transport / external side of apical plasma membrane ...biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / renal urate salt excretion / urate metabolic process / urate transmembrane transporter activity / Abacavir transmembrane transport / organic anion transport / external side of apical plasma membrane / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / export across plasma membrane / ABC-type xenobiotic transporter / Paracetamol ADME / Ciprofloxacin ADME / transepithelial transport / cellular detoxification / ABC-type xenobiotic transporter activity / NFE2L2 regulating MDR associated enzymes / Heme biosynthesis / Heme degradation / lipid transport / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / mitochondrial membrane / brush border membrane / Iron uptake and transport / transmembrane transport / membrane raft / apical plasma membrane / ATP hydrolysis activity / protein homodimerization activity / nucleoplasm / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
ABC transporter family G domain / ABC-2 type transporter / ABC-2 type transporter / ABC-2 type transporter / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-BWQ / Broad substrate specificity ATP-binding cassette transporter ABCG2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.56 Å
AuthorsJackson, 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 Switzerland, 2items
OrganizationGrant numberCountry
SNSF NCCR TransCure Switzerland
ETH ZurichETH-22-14-1 Switzerland
CitationJournal: Nat Struct Mol Biol / Year: 2018
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
DepositionJan 6, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 11, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 18, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Dec 11, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]

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Structure visualization

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Assembly

Deposited unit
A: ATP-binding cassette sub-family G member 2
B: ATP-binding cassette sub-family G member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,8394
Polymers146,7912
Non-polymers1,0472
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5650 Å2
ΔGint-35 kcal/mol
Surface area46940 Å2
MethodPISA

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Components

#1: Protein ATP-binding cassette sub-family G member 2 / Breast cancer resistance protein / CDw338 / Mitoxantrone resistance-associated protein / Placenta- ...Breast cancer resistance protein / CDw338 / Mitoxantrone resistance-associated protein / Placenta-specific ATP-binding cassette transporter / Urate exporter


Mass: 73395.742 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): HEK293-EBNA / Production host: Homo sapiens (human) / References: UniProt: Q9UNQ0
#2: Chemical ChemComp-BWQ / ~{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


Mass: 523.664 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H41N3O5

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Nanodisc-reconstituted ABCG2 in complex with MZ29 inhibitor
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 100 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS
Image scansMovie frames/image: 50 / Used frames/image: 2-50

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Processing

EM software
IDNameCategory
1Gautomatchparticle selection
2SerialEMimage acquisition
4CTFFINDCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2098186
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.56 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 402348 / Symmetry type: POINT

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