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- EMDB-18016: ABCG2 in complex with ko143 and 5D3 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-18016
TitleABCG2 in complex with ko143 and 5D3 Fab
Map data
Sample
  • Complex: ABCG2 in complex with ko143 and 5D3 Fab
    • Protein or peptide: 5d3(fab) heavy chain variable domain
    • Protein or peptide: 5D3(Fab) light chain variable domain
    • Protein or peptide: Broad substrate specificity ATP-binding cassette transporter ABCG2
  • Ligand: CHOLESTEROL
  • Ligand: tert-butyl 3-[(2S,5S,8S)-14-methoxy-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
  • Ligand: water
KeywordsMultidrug transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / sphingolipid transporter activity / renal urate salt excretion / Abacavir transmembrane transport / urate metabolic process / urate transmembrane transporter activity / external side of apical plasma membrane ...biotin transmembrane transporter activity / biotin transport / riboflavin transport / riboflavin transmembrane transporter activity / sphingolipid transporter activity / renal urate salt excretion / Abacavir transmembrane transport / urate metabolic process / urate transmembrane transporter activity / external side of apical plasma membrane / sphingolipid biosynthetic process / organic anion transport / 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 / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / mitochondrial membrane / brush border membrane / Iron uptake and transport / transmembrane transport / membrane raft / apical plasma membrane / protein homodimerization activity / ATP hydrolysis 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
Broad substrate specificity ATP-binding cassette transporter ABCG2
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsYu Q / Kowal J / Tajkhorshid E / Altmann KH / Locher KP
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: ACS Chem Biol / Year: 2024
Title: Modulation of ABCG2 Transporter Activity by Ko143 Derivatives.
Authors: Qin Yu / Sepehr Dehghani-Ghahnaviyeh / Ali Rasouli / Anna Sadurni / Julia Kowal / Rose Bang-Soerensen / Po-Chao Wen / Melanie Tinzl-Zechner / Rossitza N Irobalieva / Dongchun Ni / Henning ...Authors: Qin Yu / Sepehr Dehghani-Ghahnaviyeh / Ali Rasouli / Anna Sadurni / Julia Kowal / Rose Bang-Soerensen / Po-Chao Wen / Melanie Tinzl-Zechner / Rossitza N Irobalieva / Dongchun Ni / Henning Stahlberg / Karl-Heinz Altmann / Emad Tajkhorshid / Kaspar P Locher /
Abstract: ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic ...ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved stability.
History
DepositionJul 25, 2023-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18016.png

Downloads & links

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Map

FileDownload / File: emd_18016.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 384 pix.
= 253.44 Å		0.66 Å/pix.
x 384 pix.
= 253.44 Å		0.66 Å/pix.
x 384 pix.
= 253.44 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.66 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.001
Minimum - Maximum-0.02514581 - 0.058108136
Average (Standard dev.)0.00013072674 (±0.0014088273)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18016_msk_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_18016_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_18016_half_map_2.map
Projections & Slices
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Sample components

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Entire : ABCG2 in complex with ko143 and 5D3 Fab

EntireName: ABCG2 in complex with ko143 and 5D3 Fab
Components
  • Complex: ABCG2 in complex with ko143 and 5D3 Fab
    • Protein or peptide: 5d3(fab) heavy chain variable domain
    • Protein or peptide: 5D3(Fab) light chain variable domain
    • Protein or peptide: Broad substrate specificity ATP-binding cassette transporter ABCG2
  • Ligand: CHOLESTEROL
  • Ligand: tert-butyl 3-[(2S,5S,8S)-14-methoxy-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
  • Ligand: water

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Supramolecule #1: ABCG2 in complex with ko143 and 5D3 Fab

SupramoleculeName: ABCG2 in complex with ko143 and 5D3 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 244 KDa

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Macromolecule #1: 5d3(fab) heavy chain variable domain

MacromoleculeName: 5d3(fab) heavy chain variable domain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.843633 KDa
SequenceString: QVQLQESGPG LVKPSQSLSL TCTVTGFSIT SDYAWNWIRQ FPGKKLEWMG YINFDGGTTY NPSLRGRISI TRDTSKNQFF LQLRSVTPE DTATYYCATF YGAKGTLDYW GQGTSVTVSS AKTTPPSVYP LAPVCGDTSG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG ...String:
QVQLQESGPG LVKPSQSLSL TCTVTGFSIT SDYAWNWIRQ FPGKKLEWMG YINFDGGTTY NPSLRGRISI TRDTSKNQFF LQLRSVTPE DTATYYCATF YGAKGTLDYW GQGTSVTVSS AKTTPPSVYP LAPVCGDTSG SSVTLGCLVK GYFPEPVTLT W NSGSLSSG VHTFPAVLQS DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKIEP RGP

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Macromolecule #2: 5D3(Fab) light chain variable domain

MacromoleculeName: 5D3(Fab) light chain variable domain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.594016 KDa
SequenceString: DIVLTQSPSS FSVSLGDRVT ISCKASGYIL NRLAWYQQKP GNAPRLLISG ATSLETGFPS RFSGTGSGKD YTLSISSLQT EDVGTYYCQ QYWSTPWTFG GGTKLEIRRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
DIVLTQSPSS FSVSLGDRVT ISCKASGYIL NRLAWYQQKP GNAPRLLISG ATSLETGFPS RFSGTGSGKD YTLSISSLQT EDVGTYYCQ QYWSTPWTFG GGTKLEIRRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC

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Macromolecule #3: Broad substrate specificity ATP-binding cassette transporter ABCG2

MacromoleculeName: Broad substrate specificity ATP-binding cassette transporter ABCG2
type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.526938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKG SSSSNVEVFI PVSQGNTNGF PATASNDLKA FTEGAVLSFH NICYRVKLKS GFLPCRKPVE KEILSNINGI MKPGLNAIL GPTGGGKSSL LDVLAARKDP SGLSGDVLIN GAPRPANFKC NSGYVVQDDV VMGTLTVREN LQFSAALRLA T TMTNHEKN ...String:
MDYKDDDDKG SSSSNVEVFI PVSQGNTNGF PATASNDLKA FTEGAVLSFH NICYRVKLKS GFLPCRKPVE KEILSNINGI MKPGLNAIL GPTGGGKSSL LDVLAARKDP SGLSGDVLIN GAPRPANFKC NSGYVVQDDV VMGTLTVREN LQFSAALRLA T TMTNHEKN ERINRVIQEL GLDKVADSKV GTQFIRGVSG GERKRTSIGM ELITDPSILF LDEPTTGLDS STANAVLLLL KR MSKQGRT IIFSIHQPRY SIFKLFDSLT LLASGRLMFH GPAQEALGYF ESAGYHCEAY NNPADFFLDI INGDSTAVAL NRE EDFKAT EIIEPSKQDK PLIEKLAEIY VNSSFYKETK AELHQLSGGE KKKKITVFKE ISYTTSFCHQ LRWVSKRSFK NLLG NPQAS IAQIIVTVVL GLVIGAIYFG LKNDSTGIQN RAGVLFFLTT NQCFSSVSAV ELFVVEKKLF IHEYISGYYR VSSYF LGKL LSDLLPMRML PSIIFTCIVY FMLGLKPKAD AFFVMMFTLM MVAYSASSMA LAIAAGQSVV SVATLLMTIC FVFMMI FSG LLVNLTTIAS WLSWLQYFSI PRYGFTALQH NEFLGQNFCP GLNATGNNPC NYATCTGEEY LVKQGIDLSP WGLWKNH VA LACMIVIFLT IAYLKLLFLK KYS

UniProtKB: Broad substrate specificity ATP-binding cassette transporter ABCG2

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 10 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: tert-butyl 3-[(2S,5S,8S)-14-methoxy-2-(2-methylpropyl)-4,7-bis(ox...

MacromoleculeName: tert-butyl 3-[(2S,5S,8S)-14-methoxy-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: 6 / Number of copies: 2 / Formula: I3O
Molecular weightTheoretical: 469.573 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 33 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.5 / Component:
ConcentrationName
40.0 mMHEPES
150.0 mMNaCl
VitrificationCryogen name: ETHANE-PROPANE / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was mono-disperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

3953

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 174256
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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