5N6T

Thermotoga maritima family 1 glycoside hydrolase complexed with a cyclophellitol analogue transition state mimic


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 
    0.237 (Depositor), 0.240 (DCC) 
  • R-Value Work: 
    0.184 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 
    0.187 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8P2Click on this verticalbar to view details

This is version 1.4 of the entry. See complete history


Literature

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors.

Beenakker, T.J.M.Wander, D.P.A.Offen, W.A.Artola, M.Raich, L.Ferraz, M.J.Li, K.Y.Houben, J.H.P.M.van Rijssel, E.R.Hansen, T.van der Marel, G.A.Codee, J.D.C.Aerts, J.M.F.G.Rovira, C.Davies, G.J.Overkleeft, H.S.

(2017) J Am Chem Soc 139: 6534-6537

  • DOI: https://doi.org/10.1021/jacs.7b01773
  • Primary Citation of Related Structures:  
    5N6S, 5N6T

  • PubMed Abstract: 

    The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine-both covalent retaining β-glucosidase inhibitors-we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4 H 3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4 H 3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (K i = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4 H 3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.


  • Organizational Affiliation

    Department of Chemistry, University of York , Heslington, York, YO10 5DD, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-glucosidase A
A, B
468Thermotoga maritimaMutation(s): 0 
Gene Names: bglA
EC: 3.2.1.21
UniProt
Find proteins for Q08638 (Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8))
Explore Q08638 
Go to UniProtKB:  Q08638
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08638
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8P2
Query on 8P2

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B]
[(1~{R},2~{R},3~{R},4~{S},5~{R},6~{S})-3,4,5-tris(oxidanyl)-7-oxabicyclo[4.1.0]heptan-2-yl]methanediazonium
C7 H11 N2 O4
KCJIBVJCJMAQKE-GEGSFZHJSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
H [auth B]
I [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free:  0.237 (Depositor), 0.240 (DCC) 
  • R-Value Work:  0.184 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 0.187 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.839α = 90
b = 94.84β = 90
c = 112.93γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8P2Click on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Research CouncilUnited KingdomERC-2012-AdG-322942

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-01
    Type: Initial release
  • Version 1.1: 2017-05-17
    Changes: Database references
  • Version 1.2: 2017-05-24
    Changes: Database references
  • Version 1.3: 2019-02-20
    Changes: Author supporting evidence, Data collection, Derived calculations
  • Version 1.4: 2024-01-17
    Changes: Data collection, Database references, Refinement description