2VJX

Structural and biochemical evidence for a boat-like transition state in beta-mannosidases


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.162 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural and Biochemical Evidence for a Boat-Like Transition State in Beta-Mannosidases.

Tailford, L.E.Offen, W.A.Smith, N.L.Dumon, C.Moreland, C.Gratien, J.Heck, M.P.Stick, R.V.Bleriot, Y.Vasella, A.Gilbert, H.J.Davies, G.J.

(2008) Nat Chem Biol 4: 306

  • DOI: https://doi.org/10.1038/nchembio.81
  • Primary Citation of Related Structures:  
    2VJX, 2VL4, 2VMF, 2VO5, 2VOT, 2VQT, 2VQU, 2VR4

  • PubMed Abstract: 

    Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron beta-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases--an area that is emerging for anticancer therapeutics.


  • Organizational Affiliation

    Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-MANNOSIDASE
A, B
846Bacteroides thetaiotaomicron VPI-5482Mutation(s): 0 
EC: 3.2.1.25
UniProt
Find proteins for Q8AAK6 (Bacteroides thetaiotaomicron (strain ATCC 29148 / DSM 2079 / JCM 5827 / CCUG 10774 / NCTC 10582 / VPI-5482 / E50))
Explore Q8AAK6 
Go to UniProtKB:  Q8AAK6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8AAK6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IFL
Query on IFL

Download Ideal Coordinates CCD File 
C [auth A],
NA [auth B]
(3S,4R,5R)-3,4-DIHYDROXY-5-(HYDROXYMETHYL)PIPERIDIN-2-ONE
C6 H11 N O4
ARBXEMIAJIJEQI-WDCZJNDASA-N
BR
Query on BR

Download Ideal Coordinates CCD File 
CA [auth A]
DA [auth A]
EA [auth A]
FA [auth A]
GB [auth B]
CA [auth A],
DA [auth A],
EA [auth A],
FA [auth A],
GB [auth B],
HB [auth B],
KA [auth A]
BROMIDE ION
Br
CPELXLSAUQHCOX-UHFFFAOYSA-M
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth A]
AB [auth B]
BA [auth A]
BB [auth B]
CB [auth B]
AA [auth A],
AB [auth B],
BA [auth A],
BB [auth B],
CB [auth B],
D [auth A],
DB [auth B],
E [auth A],
EB [auth B],
F [auth A],
FB [auth B],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
MB [auth B],
N [auth A],
NB [auth B],
O [auth A],
OA [auth B],
OB [auth B],
P [auth A],
PA [auth B],
Q [auth A],
QA [auth B],
R [auth A],
RA [auth B],
S [auth A],
SA [auth B],
T [auth A],
TA [auth B],
U [auth A],
UA [auth B],
V [auth A],
VA [auth B],
W [auth A],
WA [auth B],
X [auth A],
XA [auth B],
Y [auth A],
YA [auth B],
Z [auth A],
ZA [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
GA [auth A]
HA [auth A]
IA [auth A]
IB [auth B]
JA [auth A]
GA [auth A],
HA [auth A],
IA [auth A],
IB [auth B],
JA [auth A],
JB [auth B],
KB [auth B],
LA [auth A],
LB [auth B],
MA [auth A],
PB [auth B],
QB [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
IFL PDBBind:  2VJX Ki: 1.10e+4 (nM) from 1 assay(s)
BindingDB:  2VJX Ki: 1.10e+4 (nM) from 1 assay(s)
Binding MOAD:  2VJX Ki: 1.10e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.162 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.366α = 90
b = 114.396β = 113.17
c = 99.677γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2008-04-01
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description