Eubacterium eligens Beta-glucuronidase

Experimental Data Snapshot

  • Resolution: 3.00 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.227 

wwPDB Validation   3D Report Full Report

This is version 1.4 of the entry. See complete history


Gut Microbial beta-Glucuronidase Inhibition via Catalytic Cycle Interception.

Pellock, S.J.Creekmore, B.C.Walton, W.G.Mehta, N.Biernat, K.A.Cesmat, A.P.Ariyarathna, Y.Dunn, Z.D.Li, B.Jin, J.James, L.I.Redinbo, M.R.

(2018) ACS Cent Sci 4: 868-879

  • DOI: https://doi.org/10.1021/acscentsci.8b00239
  • Primary Citation of Related Structures:  
    6BJQ, 6BJW, 6BO6, 6D4O

  • PubMed Abstract: 

    Microbial β-glucuronidases (GUSs) cause severe gut toxicities that limit the efficacy of cancer drugs and other therapeutics. Selective inhibitors of bacterial GUS have been shown to alleviate these side effects. Using structural and chemical biology, mass spectrometry, and cell-based assays, we establish that piperazine-containing GUS inhibitors intercept the glycosyl-enzyme catalytic intermediate of these retaining glycosyl hydrolases. We demonstrate that piperazine-based compounds are substrate-dependent GUS inhibitors that bind to the GUS-GlcA catalytic intermediate as a piperazine-linked glucuronide (GlcA, glucuronic acid). We confirm the GUS-dependent formation of inhibitor-glucuronide conjugates by LC-MS and show that methylated piperazine analogs display significantly reduced potencies. We further demonstrate that a range of approved piperazine- and piperidine-containing drugs from many classes, including those for the treatment of depression, infection, and cancer, function by the same mechanism, and we confirm through gene editing that these compounds selectively inhibit GUS in living bacterial cells. Together, these data reveal a unique mechanism of GUS inhibition and show that a range of therapeutics may impact GUS activities in the human gut.

  • Organizational Affiliation

    Department of Chemistry, Center for Integrated Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, and Integrated Program for Biological and Genome Sciences, and Departments of Biochemistry and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glycoside Hydrolase Family 2 candidate b-glucuronidase635[Eubacterium] eligens ATCC 27750Mutation(s): 0 
Gene Names: EUBELI_20590
Find proteins for C4Z6Z2 (Lachnospira eligens (strain ATCC 27750 / DSM 3376 / VPI C15-48 / C15-B4))
Explore C4Z6Z2 
Go to UniProtKB:  C4Z6Z2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupC4Z6Z2
Sequence Annotations
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Resolution: 3.00 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.227 
  • Space Group: P 64 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 179.775α = 90
b = 179.775β = 90
c = 134.929γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
HKL-3000data scaling

Structure Validation

View Full Validation Report

Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-25
    Type: Initial release
  • Version 1.1: 2019-02-06
    Changes: Data collection, Database references
  • Version 1.2: 2019-02-20
    Changes: Author supporting evidence, Data collection
  • Version 1.3: 2022-03-23
    Changes: Author supporting evidence, Database references
  • Version 1.4: 2024-05-22
    Changes: Data collection