1HLK

METALLO-BETA-LACTAMASE FROM BACTEROIDES FRAGILIS IN COMPLEX WITH A TRICYCLIC INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.159 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Identification of a series of tricyclic natural products as potent broad spectrum inhibitors of metallo-beta-lactamases

Payne, D.J.Hueso-Rodriguez, J.A.Boyd, H.Concha, N.O.Janson, C.A.Gilpin, M.Bateson, J.H.Chever, C.Niconovich, N.L.Pearson, S.Rittenhouse, S.Tew, D.Diez, E.Perez, P.de la Fuente, J.Rees, M.Rivera-Sagredo, A.

(2002) Antimicrob Agents Chemother 46: 1880-1886

  • DOI: https://doi.org/10.1128/AAC.46.6.1880-1886.2002
  • Primary Citation of Related Structures:  
    1HLK, 1KR3

  • PubMed Abstract: 

    This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-beta-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed K(i) values of 79, 17, and 3.4 microM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-beta-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-beta-lactamase (50% inhibitory concentration > 1,000 microM). The lack of activity against angiotensin-converting enzyme and serine beta-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 A. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC < or = 4 microg/ml). Consequently, this series of metallo-beta-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-beta-lactamases.


  • Organizational Affiliation

    Microbial, Musculoskeletal and Proliferative Diseases CEDD (UP1345), GlaxoSmithKline, Collegeville, Pennsylvania 19426-0989, USA. David_J_Payne@sbphrd.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-LACTAMASE, TYPE II
A, B
227Bacteroides fragilisMutation(s): 0 
EC: 3.5.2.6
UniProt
Find proteins for P25910 (Bacteroides fragilis)
Explore P25910 
Go to UniProtKB:  P25910
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25910
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
113 Binding MOAD:  1HLK Ki: 1.00e+4 (nM) from 1 assay(s)
PDBBind:  1HLK Ki: 1.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.159 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.8α = 92.8
b = 44.2β = 95.3
c = 58.5γ = 98
Software Package:
Software NamePurpose
X-GENdata scaling
X-GENdata reduction
AMoREphasing
CNSrefinement

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2001-11-30
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Advisory, Refinement description
  • Version 1.4: 2023-08-09
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description