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 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


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]
D [auth A],
E [auth A],
F [auth A],
H [auth B],
I [auth B],
J [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 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 
  • 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 


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