+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-18016 | |||||||||
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Title | ABCG2 in complex with ko143 and 5D3 Fab | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Multidrug 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 / 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 / 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 / Iron uptake and transport / mitochondrial membrane / brush border membrane / transmembrane transport / membrane raft / apical plasma membrane / protein homodimerization activity / ATP hydrolysis activity / nucleoplasm / ATP binding / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
Authors | Yu Q / Kowal J / Tajkhorshid E / Altmann KH / Locher KP | |||||||||
Funding support | Switzerland, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_18016.map.gz | 18.3 MB | EMDB map data format | |
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Header (meta data) | emd-18016-v30.xml emd-18016.xml | 18.2 KB 18.2 KB | Display Display | EMDB header |
Images | emd_18016.png | 143.8 KB | ||
Masks | emd_18016_msk_1.map | 216 MB | Mask map | |
Filedesc metadata | emd-18016.cif.gz | 6.9 KB | ||
Others | emd_18016_half_map_1.map.gz emd_18016_half_map_2.map.gz | 169.2 MB 169.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-18016 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-18016 | HTTPS FTP |
-Validation report
Summary document | emd_18016_validation.pdf.gz | 896.1 KB | Display | EMDB validaton report |
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Full document | emd_18016_full_validation.pdf.gz | 895.7 KB | Display | |
Data in XML | emd_18016_validation.xml.gz | 15.5 KB | Display | |
Data in CIF | emd_18016_validation.cif.gz | 18.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-18016 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-18016 | HTTPS FTP |
-Related structure data
Related structure data | 8py4MC 8pxoC 8q7bC 8qcmC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_18016.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.66 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_18016_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_18016_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_18016_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : ABCG2 in complex with ko143 and 5D3 Fab
Entire | Name: ABCG2 in complex with ko143 and 5D3 Fab |
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Components |
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-Supramolecule #1: ABCG2 in complex with ko143 and 5D3 Fab
Supramolecule | Name: ABCG2 in complex with ko143 and 5D3 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 244 KDa |
-Macromolecule #1: 5d3(fab) heavy chain variable domain
Macromolecule | Name: 5d3(fab) heavy chain variable domain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 23.843633 KDa |
Sequence | String: 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 |
-Macromolecule #2: 5D3(Fab) light chain variable domain
Macromolecule | Name: 5D3(Fab) light chain variable domain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 23.594016 KDa |
Sequence | String: 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 |
-Macromolecule #3: Broad substrate specificity ATP-binding cassette transporter ABCG2
Macromolecule | Name: 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 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 73.526938 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #5: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 10 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Macromolecule #6: tert-butyl 3-[(2S,5S,8S)-14-methoxy-2-(2-methylpropyl)-4,7-bis(ox...
Macromolecule | Name: 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 |
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Molecular weight | Theoretical: 469.573 Da |
-Macromolecule #7: water
Macromolecule | Name: water / type: ligand / ID: 7 / Number of copies: 33 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 1 mg/mL | ||||||
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Buffer | pH: 7.5 / Component:
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Vitrification | Cryogen name: ETHANE-PROPANE / Instrument: FEI VITROBOT MARK IV | ||||||
Details | This sample was mono-disperse |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 58.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Startup model | Type of model: EMDB MAP EMDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 174256 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |