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- EMDB-40180: MsbA bound to cerastecin C -

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Basic information

Entry
Database: EMDB / ID: EMD-40180
TitleMsbA bound to cerastecin C
Map data
Sample
  • Complex: MsbA complexed with cerastecin C
    • Protein or peptide: Lipid A export ATP-binding/permease protein MsbA
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
  • Ligand: 2-[(4-butylbenzene-1-sulfonyl)amino]-5-[(3-{4-[(4-butylbenzene-1-sulfonyl)amino]-3-carboxyanilino}-3-oxopropyl)carbamoyl]benzoic acid
KeywordsMsbA / antibacterial / inhibitor / cerastecin / ANTIMICROBIAL PROTEIN
Function / homology
Function and homology information


ATPase-coupled lipid transmembrane transporter activity / ABC-type transporter activity / ATP hydrolysis activity / ATP binding / membrane
Similarity search - Function
ABC transporter, lipid A-core flippase, MsbA / Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain ...ABC transporter, lipid A-core flippase, MsbA / Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / 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
Lipid A export ATP-binding/permease protein MsbA
Similarity search - Component
Biological speciesAcinetobacter baumannii (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsChen Y / Klein D
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Microbiol / Year: 2024
Title: Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.
Authors: Hao Wang / Andrii Ishchenko / Jason Skudlarek / Pamela Shen / Liudmila Dzhekieva / Ronald E Painter / Yun-Ting Chen / Marina Bukhtiyarova / Andrew Leithead / Rodger Tracy / Kerim Babaoglu / ...Authors: Hao Wang / Andrii Ishchenko / Jason Skudlarek / Pamela Shen / Liudmila Dzhekieva / Ronald E Painter / Yun-Ting Chen / Marina Bukhtiyarova / Andrew Leithead / Rodger Tracy / Kerim Babaoglu / Carolyn Bahnck-Teets / Alexei Buevich / Tamara D Cabalu / Marc Labroli / Henry Lange / Ying Lei / Wei Li / Jian Liu / Paul A Mann / Tao Meng / Helen J Mitchell / James Mulhearn / Giovanna Scapin / Deyou Sha / Anthony W Shaw / Qian Si / Ling Tong / Chengwei Wu / Zhe Wu / Jing Chen Xiao / Min Xu / Li-Kang Zhang / David McKenney / Randy R Miller / Todd A Black / Andrew Cooke / Carl J Balibar / Daniel J Klein / Izzat Raheem / Scott S Walker /
Abstract: Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of ...Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.
History
DepositionMar 17, 2023-
Header (metadata) releaseApr 24, 2024-
Map releaseApr 24, 2024-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40180.png

Downloads & links

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Map

FileDownload / File: emd_40180.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.18607205 - 0.47620463
Average (Standard dev.)0.0006563126 (±0.01695605)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40180_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_40180_half_map_2.map
Projections & Slices
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Sample components

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Entire : MsbA complexed with cerastecin C

EntireName: MsbA complexed with cerastecin C
Components
  • Complex: MsbA complexed with cerastecin C
    • Protein or peptide: Lipid A export ATP-binding/permease protein MsbA
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
  • Ligand: 2-[(4-butylbenzene-1-sulfonyl)amino]-5-[(3-{4-[(4-butylbenzene-1-sulfonyl)amino]-3-carboxyanilino}-3-oxopropyl)carbamoyl]benzoic acid

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Supramolecule #1: MsbA complexed with cerastecin C

SupramoleculeName: MsbA complexed with cerastecin C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Acinetobacter baumannii (bacteria)
Molecular weightTheoretical: 450 KDa

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Macromolecule #1: Lipid A export ATP-binding/permease protein MsbA

MacromoleculeName: Lipid A export ATP-binding/permease protein MsbA / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Acinetobacter baumannii (bacteria)
Molecular weightTheoretical: 66.893578 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MGHHHHHHHH HHSSGHIDDD DKHMNQDFKV YLRLISYLKP YWGVALLVLI GFGMNSATEV SVAKLIKFII DAIQNASRAD LDWFPLLII LLVFFRGLGL FMGGYYTAVI SRSLVFSIRQ EVYAKLLRLP AQYYLDNSSG HITAKIMYNV EQLTAASSES L KTIVRDGM ...String:
MGHHHHHHHH HHSSGHIDDD DKHMNQDFKV YLRLISYLKP YWGVALLVLI GFGMNSATEV SVAKLIKFII DAIQNASRAD LDWFPLLII LLVFFRGLGL FMGGYYTAVI SRSLVFSIRQ EVYAKLLRLP AQYYLDNSSG HITAKIMYNV EQLTAASSES L KTIVRDGM ITLGLLGYLF YTNWRLTICI MVFLPVIGIL VRKASKRMRK LSMQVQDTMG DVNHVVQESI NGNAVVKSFA GE ESEQERF YKSSEENLKR GLKMVIVQNL NSPVVQVVMA CAMALIVWLA LRPQILGNTT AGEFVAYITA AGLLSKPVKN LTD VNEKLQ RGLAAAHSVF ELLDLPEEQN SGELKPQLQG AIRFDHVVLN YADGTQAIKD FSLDIRPGET VALVGRSGAG KTSL VNMLV RFQEVSSGQI YLDDLPIRDI ELSSLRTQIA MVNQQVVLFN RTVRENIAYG QLHNASDEDV IAAAKAAYAH DFIMN LPNG YDTVLGAQGL NLSGGQRQRI AIARAILKNA PILILDEATS ALDNESEHFI QQAFDEAMQD RTTIVIAHRL STIENA DRI VVMDRGQIVE QGTHQELLAK HGAYYQLHQR NFEDQ

UniProtKB: Lipid A export ATP-binding/permease protein MsbA

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Macromolecule #2: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 2 / Number of copies: 2 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

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Macromolecule #3: 2-[(4-butylbenzene-1-sulfonyl)amino]-5-[(3-{4-[(4-butylbenzene-1-...

MacromoleculeName: 2-[(4-butylbenzene-1-sulfonyl)amino]-5-[(3-{4-[(4-butylbenzene-1-sulfonyl)amino]-3-carboxyanilino}-3-oxopropyl)carbamoyl]benzoic acid
type: ligand / ID: 3 / Number of copies: 1 / Formula: ZQF
Molecular weightTheoretical: 778.891 Da

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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

Concentration0.3 mg/mL
BufferpH: 7
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 62.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 4.251 µm / Nominal defocus min: 1.926 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1680369
Startup modelType of model: OTHER / Details: ab-initio model from cryosparc
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 296798
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8gk7:
MsbA bound to cerastecin C

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