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- EMDB-4281: Zosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (AB... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-4281 | ||||||||||||
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Title | Zosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) | ||||||||||||
![]() | Zosuquidar complex of ABCB1HM-X. Final post-processed map after partial detergent belt removal. | ||||||||||||
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Function / homology | ![]() positive regulation of anion channel activity / ABC-type oligopeptide transporter activity / ceramide translocation / terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | ||||||||||||
Method | ![]() ![]() | ||||||||||||
![]() | Alam A / Locher KP | ||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1. Authors: Amer Alam / Raphael Küng / Julia Kowal / Robert A McLeod / Nina Tremp / Eugenia V Broude / Igor B Roninson / Henning Stahlberg / Kaspar P Locher / ![]() ![]() Abstract: The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer ...The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes. | ||||||||||||
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 | ![]() | 153.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.6 KB 15.6 KB | Display Display | ![]() |
Images | ![]() | 149.2 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6fn1MC ![]() 4282C ![]() 4283C ![]() 4284C ![]() 4285C ![]() 6fn4C 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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Annotation | Zosuquidar complex of ABCB1HM-X. Final post-processed map after partial detergent belt removal. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.84 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 : Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zo...
Entire | Name: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar |
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Components |
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-Supramolecule #1: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zo...
Supramolecule | Name: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Molecular weight | Theoretical: 195 KDa |
-Supramolecule #2: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zo...
Supramolecule | Name: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Supramolecule #3: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zo...
Supramolecule | Name: Human-mouse chimeric ABCB1 (ABCB1HM) complex with UIC2 fab and zosuquidar type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3 |
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Source (natural) | Organism: ![]() ![]() ![]() |
Recombinant expression | Organism: ![]() ![]() ![]() |
-Macromolecule #1: Human-mouse chimeric ABCB1 (ABCBHM)
Macromolecule | Name: Human-mouse chimeric ABCB1 (ABCBHM) / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 137.719953 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMSN ITNRSDINDT GFFMNLEEDM TTYAYYYTG IGAGVLIVAY IQVSFWLLAA GRQIHKIRQK FFHAIMNQEI GWFDVHDVGE LNTRLTDDVS KINEGIGDKI G MFFQAMAT ...String: PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGEMTDIFAN AGNLEDLMSN ITNRSDINDT GFFMNLEEDM TTYAYYYTG IGAGVLIVAY IQVSFWLLAA GRQIHKIRQK FFHAIMNQEI GWFDVHDVGE LNTRLTDDVS KINEGIGDKI G MFFQAMAT FFGGFIIGFT RGWKLTLVIL AISPVLGLSA GIWAKILSSF TDKELHAYAK AGAVAEEVLA AIRTVIAFGG QK KELERYN NNLEEAKRLG IKKAITANIS MGAAFLLIYA SYALAFWYGT TLVLSGEYSI GQVLTVFFSV LIGAFSVGQA SPN IEAFAN ARGAAYEVFK IIDNKPSIDS FSKSGHKPDN IQGNLEFKNI HFSYPSRKEV QILKGLNLKV KSGQTVALVG NSGA GKSTT VQLMQRLYDP LDGMVSIDGQ DIRTINVRYL REIIGVVSQE PVLFATTIAE NIRYGREDVT MDEIEKAVKE ANAYD FIMK LPHQFDTLVG ERGAQLSGGQ KQRIAIARAL VRNPKILLLD EATCALDTES EAVVQAALDK AREGRTTIVI AHRLST VRN ADVIAGFDGG VIVEQGNHDE LMREKGIYFK LVMTQTAGNE IELGNEAAKS KDEIDNLDMS SKDSGSSLIR RRSTRKS IA GPHDQDRKLS TKEALDEDVP PASFWRILKL NSTEWPYFVV GIFVAIINGG LQPAFSVIFS KIIGVFTRID DPETKRQN S NLFSLLFLIL GIISFITFFL QGFTFGKAGE ILTKRLRYMV FKSMLRQDVS WFDDPKNTTG ALTTRLANDA AQVKGATGS RLAVIFQNIA NLGTGIIISF IYGWQLTLLL LAIVPIIAIA GVVEMKMLSG QALKDKKELE GSGKIATEAI ENFRTVVSLT REQKFETMY AQSLQIPYRN AMKKAHVFGI TFSFTQAMMY FSYAAAFRFG AYLVAHKLMS FEDVLLVFSA IVFGAMAVGQ V SSFAPDYA KATVSASHII RIIEKTPEID SYSTQGLKPN MLEGNVQFSG VVFNYPTRPS IPVLQGLSLE VKKGQTLALV GS SGAGKST VVQLLERFYD PMAGSVFLDG KEIKQLNVQW LRAQLGIVSQ EPILFDTSIA ENIAYGDNSR VVSYEEIVRA AKE ANIHQF IDSLPDKYNT RVGDKGTQLS GGQKQRIAIA RALVRQPHIL LLDEATCALD TESEKVVQEA LDKAREGRTT IVIA HRLST IQNADLIVVI QNGKVKEHGT HQQLLAQKGI YFSMVSVQAG AKRS |
-Macromolecule #2: UIC2 Antigen Binding Fragment Light chain
Macromolecule | Name: UIC2 Antigen Binding Fragment Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 24.321039 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: QVVMTQSPLS LPVSLGDQAS ISCRSSQSLL HSNGNTYLHW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYFCSQSTHI PPWTFGGGTK LDIKRADAAP TVSIFPPSSE QLTSGGLSVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS ...String: QVVMTQSPLS LPVSLGDQAS ISCRSSQSLL HSNGNTYLHW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYFCSQSTHI PPWTFGGGTK LDIKRADAAP TVSIFPPSSE QLTSGGLSVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS WTDQDSKDST YSMSSTLTLT KDEYERHNSY TCEATHKTST SPIVKSFNRN EC |
-Macromolecule #3: UIC2 Antigen Binding Fragment Heavy Chain
Macromolecule | Name: UIC2 Antigen Binding Fragment Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 24.381281 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: EVQLQESGPE LVKTGASVKI SCKASGYSFS NYYIHWVKQS HGKSLEWIGF ISCYNGATFY NQKFKGKATF TVDNSSSTAY MKFNSLTFE DSAVYYCARL PIQFGNFYPM DYWGQGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC LVKGYFPEPV T LTWNSGSL ...String: EVQLQESGPE LVKTGASVKI SCKASGYSFS NYYIHWVKQS HGKSLEWIGF ISCYNGATFY NQKFKGKATF TVDNSSSTAY MKFNSLTFE DSAVYYCARL PIQFGNFYPM DYWGQGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC LVKGYFPEPV T LTWNSGSL SSGVHTFPAV LQSDLYTLSS SVTVTSSTWP SQSITCNVAH PASSTKVDKK IEPRGPT |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 3 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #5: Zosuquidar
Macromolecule | Name: Zosuquidar / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZQU |
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Molecular weight | Theoretical: 527.604 Da |
Chemical component information | ![]() ChemComp-ZQU: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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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![]() |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 1.54 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Initial angle assignment | Type: PROJECTION MATCHING |
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Final angle assignment | Type: PROJECTION MATCHING |
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 231969 |