5W13

ADC-7 in complex with boronic acid transition state inhibitor SM23


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Inhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel beta-Lactamase Inhibitors.

Caselli, E.Romagnoli, C.Powers, R.A.Taracila, M.A.Bouza, A.A.Swanson, H.C.Smolen, K.A.Fini, F.Wallar, B.J.Bonomo, R.A.Prati, F.

(2018) ACS Infect Dis 4: 337-348

  • DOI: https://doi.org/10.1021/acsinfecdis.7b00153
  • Primary Citation of Related Structures:  
    5W12, 5W13, 5W14

  • PubMed Abstract: 

    Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound S02030 ( K i = 44 nM) proved to be a good lead compound against ADC-7 ( Acinetobacter-derived cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C 3 /C 4 found in β-lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a-c, 3h, and 3j, K i = 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d ( K i = 224 nM) and the hydroxyamide derivative 3e ( K i = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030 but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than a binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic.


  • Organizational Affiliation

    Department of Life Sciences , University of Modena and Reggio Emilia , Via Campi 101 , 41125 , Modena , Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-lactamase
A, B, C, D
361Acinetobacter baumanniiMutation(s): 0 
EC: 3.5.2.6
UniProt
Find proteins for Q6DRA1 (Acinetobacter baumannii)
Explore Q6DRA1 
Go to UniProtKB:  Q6DRA1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6DRA1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SM2 BindingDB:  5W13 Ki: 21.1 (nM) from 1 assay(s)
Kd: 90 (nM) from 1 assay(s)
-TΔS: -1.75e+1 (kJ/mol) from 1 assay(s)
ΔH: -2.30e+1 (kJ/mol) from 1 assay(s)
ΔG: -4.02e+1 (kJ/mol) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.712α = 90
b = 81.651β = 112.84
c = 106.415γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR01 AI072219

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-29
    Type: Initial release
  • Version 1.1: 2017-12-20
    Changes: Database references
  • Version 1.2: 2018-03-21
    Changes: Database references
  • Version 1.3: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description