6D4O

Eubacterium eligens beta-glucuronidase bound to an amoxapine-glucuronide conjugate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

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 Pharmacological Sciences, Icahn School of Medicine at Mt. Sinai, New York, New York 10029, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-glucuronidase614Lachnospira eligensMutation(s): 0 
Gene Names: uidAERS852490_00568ERS852492_02599
EC: 3.2.1.31
UniProt
Find proteins for A0A174ZZA3 (Lachnospira eligens)
Explore A0A174ZZA3 
Go to UniProtKB:  A0A174ZZA3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A174ZZA3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FUV (Subject of Investigation/LOI)
Query on FUV

Download Ideal Coordinates CCD File 
B [auth A](5aR,9aR)-2-chloro-11-(4-beta-D-glucopyranuronosylpiperazin-1-yl)-5a,6,9,9a-tetrahydrodibenzo[b,f][1,4]oxazepine
C23 H28 Cl N3 O7
OXNRDDVCZKYHOL-IBISMJPWSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 
  • Space Group: P 64 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 179.954α = 90
b = 179.954β = 90
c = 134.941γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA098468
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA207416

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-25
    Type: Initial release
  • Version 1.1: 2018-08-22
    Changes: Data collection, Database references
  • Version 1.2: 2019-12-04
    Changes: Author supporting evidence