4UR9

Structure of ligand bound glycosylhydrolase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 

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This is version 2.0 of the entry. See complete history


Literature

Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase.

Darby, J.F.Landstrom, J.Roth, C.He, Y.Davies, G.J.Hubbard, R.E.

(2014) Angew Chem Int Ed Engl 53: 13419

  • DOI: https://doi.org/10.1002/anie.201407081
  • Primary Citation of Related Structures:  
    4UR9

  • PubMed Abstract: 

    Fragment-based approaches are used routinely to discover enzyme inhibitors as cellular tools and potential therapeutic agents. There have been few reports, however, of the discovery of small-molecule enzyme activators. Herein, we describe the discovery and characterization of small-molecule activators of a glycoside hydrolase (a bacterial O-GlcNAc hydrolase). A ligand-observed NMR screen of a library of commercially available fragments identified an enzyme activator which yielded an approximate 90 % increase in kcat /KM  values (kcat =catalytic rate constant; KM =Michaelis constant). This compound binds to the enzyme in close proximity to the catalytic center. Evolution of the initial hits led to improved compounds that behave as nonessential activators effecting both KM  and Vmax  values (Vmax =maximum rate of reaction). The compounds appear to stabilize an active "closed" form of the enzyme. Such activators could offer an orthogonal alternative to enzyme inhibitors for perturbation of enzyme activity in vivo, and could also be used for glycoside hydrolase activation in many industrial processes.


  • Organizational Affiliation

    York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD (UK).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
O-GLCNACASE BT_4395
A, B
716Bacteroides thetaiotaomicronMutation(s): 0 
EC: 3.2.1.169
UniProt
Find proteins for Q89ZI2 (Bacteroides thetaiotaomicron (strain ATCC 29148 / DSM 2079 / JCM 5827 / CCUG 10774 / NCTC 10582 / VPI-5482 / E50))
Explore Q89ZI2 
Go to UniProtKB:  Q89ZI2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ89ZI2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
BK9 Binding MOAD:  4UR9 Kd: 3.10e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.486α = 90
b = 162.735β = 90
c = 223.179γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-25
    Type: Initial release
  • Version 2.0: 2019-10-23
    Changes: Atomic model, Data collection, Other