7M4P

Multidrug Efflux pump AdeJ with Eravacycline bound


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.86 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 2.2 of the entry. See complete history


Literature

Cryo-EM Determination of Eravacycline-Bound Structures of the Ribosome and the Multidrug Efflux Pump AdeJ of Acinetobacter baumannii.

Zhang, Z.Morgan, C.E.Bonomo, R.A.Yu, E.W.

(2021) mBio 12: e0103121-e0103121

  • DOI: https://doi.org/10.1128/mBio.01031-21
  • Primary Citation of Related Structures:  
    7M4P, 7M4Q, 7M4U, 7M4V, 7M4W, 7M4X, 7M4Y, 7M4Z

  • PubMed Abstract: 

    Antibiotic-resistant strains of the Gram-negative pathogen Acinetobacter baumannii have emerged as a significant global health threat. One successful therapeutic option to treat bacterial infections has been to target the bacterial ribosome. However, in many cases, multidrug efflux pumps within the bacterium recognize and extrude these clinically important antibiotics designed to inhibit the protein synthesis function of the bacterial ribosome. Thus, multidrug efflux within A. baumannii and other highly drug-resistant strains is a major cause of failure of drug-based treatments of infectious diseases. We here report the first structures of the A cinetobacter d rug e fflux (Ade)J pump in the presence of the antibiotic eravacycline, using single-particle cryo-electron microscopy (cryo-EM). We also describe cryo-EM structures of the eravacycline-bound forms of the A. baumannii ribosome, including the 70S, 50S, and 30S forms. Our data indicate that the AdeJ pump primarily uses hydrophobic interactions to bind eravacycline, while the 70S ribosome utilizes electrostatic interactions to bind this drug. Our work here highlights how an antibiotic can bind multiple bacterial targets through different mechanisms and potentially enables drug optimization by taking advantage of these different modes of ligand binding. IMPORTANCE Acinetobacter baumannii has developed into a highly antibiotic-resistant Gram-negative pathogen. The prevalent AdeJ multidrug efflux pump mediates resistance to different classes of antibiotics known to inhibit the function of the 70S ribosome. Here, we report the first structures of the A. baumannii AdeJ pump, both in the absence and presence of eravacycline. We also describe structures of the A. baumannii ribosome bound by this antibiotic. Our results indicate that AdeJ and the ribosome use very distinct binding modes for drug recognition. Our work will ultimately enable structure-based drug discovery to combat antibiotic-resistant A. baumannii infection.


  • Organizational Affiliation

    Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Efflux pump membrane transporter
A, B, C
1,058Acinetobacter baumanniiMutation(s): 0 
Gene Names: adeJmexB_1mexB_2
Membrane Entity: Yes 
UniProt
Find proteins for Q2FD94 (Acinetobacter baumannii)
Explore Q2FD94 
Go to UniProtKB:  Q2FD94
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ2FD94
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3PE
Query on 3PE

Download Ideal Coordinates CCD File 
D [auth A]
E [auth B]
F [auth B]
G [auth B]
H [auth B]
D [auth A],
E [auth B],
F [auth B],
G [auth B],
H [auth B],
J [auth C],
K [auth C],
L [auth C]
1,2-Distearoyl-sn-glycerophosphoethanolamine
C41 H82 N O8 P
LVNGJLRDBYCPGB-LDLOPFEMSA-N
YQM (Subject of Investigation/LOI)
Query on YQM

Download Ideal Coordinates CCD File 
I [auth B]Eravacycline
C27 H31 F N4 O8
AKLMFDDQCHURPW-ISIOAQNYSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.86 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data

  • Released Date: 2021-05-19 
  • Deposition Author(s): Zhang, Z.

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2021-05-19
    Type: Initial release
  • Version 2.0: 2021-09-01
    Changes: Atomic model, Database references, Derived calculations, Structure summary
  • Version 2.1: 2022-03-02
    Changes: Structure summary
  • Version 2.2: 2024-05-29
    Changes: Data collection