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Open data
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Basic information
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Title | Acinetobacter baylyi LptB2FG bound to lipopolysaccharide and RG6006 | ||||||||||||
![]() | Acinetobacter baylyi LptB2FG bound to LPS and Zosurabalpin | ||||||||||||
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Function / homology | ![]() lipopolysaccharide transport / ATP-binding cassette (ABC) transporter complex / transmembrane transport / ![]() ![]() ![]() Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() | ||||||||||||
Method | ![]() ![]() | ||||||||||||
![]() | Pahil KS / Gilman MSA / Kruse AC / Kahne D | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Authors: Karanbir S Pahil / Morgan S A Gilman / Vadim Baidin / Thomas Clairfeuille / Patrizio Mattei / Christoph Bieniossek / Fabian Dey / Dieter Muri / Remo Baettig / Michael Lobritz / Kenneth ...Authors: Karanbir S Pahil / Morgan S A Gilman / Vadim Baidin / Thomas Clairfeuille / Patrizio Mattei / Christoph Bieniossek / Fabian Dey / Dieter Muri / Remo Baettig / Michael Lobritz / Kenneth Bradley / Andrew C Kruse / Daniel Kahne / ![]() ![]() Abstract: Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature ...Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens. | ||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 25.7 KB 25.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 8.5 KB | Display | ![]() |
Images | ![]() | 68 KB | ||
Filedesc metadata | ![]() | 7.4 KB | ||
Others | ![]() ![]() ![]() | 59.8 MB 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8frnMC ![]() 8frlC ![]() 8frmC ![]() 8froC ![]() 8frpC ![]() 8ufgC ![]() 8ufhC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | Acinetobacter baylyi LptB2FG bound to LPS and Zosurabalpin | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Acinetobacter baylyi LptB2FG bound to LPS and Zosurabalpin...
File | emd_29402_additional_1.map | ||||||||||||
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Annotation | Acinetobacter baylyi LptB2FG bound to LPS and Zosurabalpin with the detergent micelle and periplasmic domains masked out. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: First half map
File | emd_29402_half_map_1.map | ||||||||||||
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Annotation | First half map | ||||||||||||
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Density Histograms |
-Half map: Second half map
File | emd_29402_half_map_2.map | ||||||||||||
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Annotation | Second half map | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Inner membrane lipopolysaccharide transporter composed of LptF, L...
Entire | Name: Inner membrane lipopolysaccharide transporter composed of LptF, LptG and two molecules of LptB in complex with lipopolysaccharide and Zosurabalpin |
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Components |
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-Supramolecule #1: Inner membrane lipopolysaccharide transporter composed of LptF, L...
Supramolecule | Name: Inner membrane lipopolysaccharide transporter composed of LptF, LptG and two molecules of LptB in complex with lipopolysaccharide and Zosurabalpin type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 139.483 KDa |
-Macromolecule #1: Lipopolysaccharide export system ATP-binding protein LptB
Macromolecule | Name: Lipopolysaccharide export system ATP-binding protein LptB type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 29.032344 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: MHHHHHHHME QIAQQQPQTL CIKHLAKNYS KRWVVKDVSF EMQSGQIVGL LGPNGAGKTT SFYMVVGLVR MDKGEIHLDN LDLSDLAMH ERARKGIGYL PQEASIFRKL TIAENIMAIL ETRKDLNKQQ RQQRLQELLN DFKITHIKDS LGMSVSGGER R RAEIARAL ...String: MHHHHHHHME QIAQQQPQTL CIKHLAKNYS KRWVVKDVSF EMQSGQIVGL LGPNGAGKTT SFYMVVGLVR MDKGEIHLDN LDLSDLAMH ERARKGIGYL PQEASIFRKL TIAENIMAIL ETRKDLNKQQ RQQRLQELLN DFKITHIKDS LGMSVSGGER R RAEIARAL AADPKFMLLD EPFAGVDPIS VGDIKDIIRN LKDRGIGVLI TDHNVRETLA ICEHAYIVSE GAVIAEGSPQ DI LENEQVR KVYLGDDFTV UniProtKB: Lipopolysaccharide export system ATP-binding protein LptB |
-Macromolecule #2: Lipopolysaccharide export system permease protein LptF
Macromolecule | Name: Lipopolysaccharide export system permease protein LptF type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 41.564273 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: MIIRRYLVKQ VVSTSLVVIA LLTLIMMGGR LIKYFGVAAQ GRLDAGVLFS IIGYRMPEFL TLILPLGFFI GLMLVFGRLY VDHEMAVLN GSGISRIRLG QLLIPLALVF LVIQGILMLW MTPWGLRQFD QLSSSQAVRT GFDLVRPKEF ISSGPYTIYA G DLSEDRKN ...String: MIIRRYLVKQ VVSTSLVVIA LLTLIMMGGR LIKYFGVAAQ GRLDAGVLFS IIGYRMPEFL TLILPLGFFI GLMLVFGRLY VDHEMAVLN GSGISRIRLG QLLIPLALVF LVIQGILMLW MTPWGLRQFD QLSSSQAVRT GFDLVRPKEF ISSGPYTIYA G DLSEDRKN LKDIFFYQRA QKEGKPDVMI LAKEATRVVM ENETANVVDL IQGRRYEIYP GKAKYSQAEF QRYRLRLEND KS ATFETDK VEALPSSKLW NKWNDPVIAS EMGWRVFGPF TIVIALMMAV ALCEVSPRQG RYYRLIPAIF IFASLIVLLI AIR TRISRD ELGVWAYPAA LAVYGIAAAL FSRKQKLAPK IKKQIKRVRA UniProtKB: Lipopolysaccharide export system permease protein LptF |
-Macromolecule #3: LPS export ABC transporter permease LptG
Macromolecule | Name: LPS export ABC transporter permease LptG / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 40.080621 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: MLARRIVAKH VTKTTALAML GTTIVLVILQ VLFTYLGELS NLKADYSAWQ AFLYVLWGAP RYLYEILPIS ALIGAILGLG TLASNSELI VMRSVGISLW RIVGWVIRSA LVLVLLSFAL SEWVVPYTNE RANSVKSHQS VAALGEVRGY WSREGQRFIY V DYANSQGQ ...String: MLARRIVAKH VTKTTALAML GTTIVLVILQ VLFTYLGELS NLKADYSAWQ AFLYVLWGAP RYLYEILPIS ALIGAILGLG TLASNSELI VMRSVGISLW RIVGWVIRSA LVLVLLSFAL SEWVVPYTNE RANSVKSHQS VAALGEVRGY WSREGQRFIY V DYANSQGQ LKRIQVVDFD DNYRLKSVTN AEQGQFVKDG QWLLNHSQQM AIQGQGDAVL ANAAKQPFSL ALQPKYVHMV TI DPEDLSF SQLVSFMNYM REYSQVPKTY QLAFWKKVAS PFALITLVLV ACSFIFGPLR QQSMGFRLVI ALFIGLGFYY LQD FLGYAS LVYNPSPAWF VLGPIVLMFV AGSYLLYRAR UniProtKB: ![]() |
-Macromolecule #4: (2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-[(...
Macromolecule | Name: (2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-[(2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-5-[(2~{S},3~{S},4~{R},5~{R},6~{R})-6-[(1~{S})-1,2-bis(oxidanyl)ethyl] ...Name: (2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-[(2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-5-[(2~{S},3~{S},4~{R},5~{R},6~{R})-6-[(1~{S})-1,2-bis(oxidanyl)ethyl]-4-[(2~{R},3~{S},4~{R},5~{S},6~{R})-6-[(1~{S})-2-[(2~{S},3~{S},4~{S},5~{S},6~{R})-6-[(1~{S})-1,2-bis(oxidanyl)ethyl]-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-1-oxidanyl-ethyl]-3,4-bis(oxidanyl)-5-phosphonooxy-oxan-2-yl]oxy-3-oxidanyl-5-phosphonooxy-oxan-2-yl]oxy-2-carboxy-2-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-5-[[(3~{R})-3-dodecanoyloxytetradecanoyl]amino]-6-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-3-oxidanyl-5-[[(3~{R})-3-oxidanyltetradecanoyl]amino]-4-[(3~{R})-3-oxidanyltetradecanoyl]oxy-6-phosphonooxy-oxan-2-yl]methoxy]-3-phosphonooxy-4-[(3~{R})-3-tetradecanoyloxytetradecanoyl]oxy-oxan-2-yl]methoxy]oxan-4-yl]oxy-4,5-bis(oxidanyl)oxane-2-carboxylic acid type: ligand / ID: 4 / Number of copies: 1 / Formula: JSG |
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Molecular weight | Theoretical: 2.975178 KDa |
Chemical component information | ![]() ChemComp-JSG: |
-Macromolecule #5: Zosurabalpin
Macromolecule | Name: Zosurabalpin / type: ligand / ID: 5 / Number of copies: 1 / Formula: VB6 |
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Molecular weight | Theoretical: 790.973 Da |
Chemical component information | ![]() ChemComp-VB6: |
-Macromolecule #6: DODECYL-BETA-D-MALTOSIDE
Macromolecule | Name: DODECYL-BETA-D-MALTOSIDE / type: ligand / ID: 6 / Number of copies: 1 / Formula: LMT |
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Molecular weight | Theoretical: 510.615 Da |
Chemical component information | ![]() ChemComp-LMT: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 7.5 mg/mL | |||||||||||||||
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Buffer | pH: 7.4 Component:
Details: 300 mM NaCl, 20 mM Tris [pH 7.4], 0.02% GDN, 0.25 mM tris(hydroxypropyl)phosphine | |||||||||||||||
Grid | Model: C-flat-1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE | |||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV | |||||||||||||||
Details | This sample was monodisperse as determined by SEC. |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.2 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |