4B7Z

Mus musculus Acetylcholinesterase in complex with N-(2-Diethylamino-ethyl)-1-(4-methylphenyl)-methanesulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors.

Andersson, C.D.Forsgren, N.Akfur, C.Allgardsson, A.Berg, L.Engdahl, C.Qian, W.Ekstrom, F.J.Linusson, A.

(2013) J Med Chem 56: 7615

  • DOI: https://doi.org/10.1021/jm400990p
  • Primary Citation of Related Structures:  
    4B7Z, 4B80, 4B81, 4B82, 4B83, 4B84, 4B85, 4BTL

  • PubMed Abstract: 

    The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.


  • Organizational Affiliation

    Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINESTERASE
A, B
548Mus musculusMutation(s): 0 
EC: 3.1.1.7
UniProt & NIH Common Fund Data Resources
Find proteins for P21836 (Mus musculus)
Explore P21836 
Go to UniProtKB:  P21836
IMPC:  MGI:87876
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21836
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Q4Q
Query on Q4Q

Download Ideal Coordinates CCD File 
C [auth A],
O [auth B]
N-[2-(diethylamino)ethyl]-1-(4-methylphenyl)methanesulfonamide
C14 H24 N2 O2 S
LLYDBPSCQPGQNQ-UHFFFAOYSA-N
P6G
Query on P6G

Download Ideal Coordinates CCD File 
E [auth A]HEXAETHYLENE GLYCOL
C12 H26 O7
IIRDTKBZINWQAW-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
G [auth A],
I [auth A],
S [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
D [auth A]
F [auth A]
H [auth A]
J [auth A]
K [auth A]
D [auth A],
F [auth A],
H [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
P [auth B],
Q [auth B],
R [auth B],
T [auth B],
V [auth B],
W [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
N [auth A],
U [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
Q4Q PDBBind:  4B7Z IC50: 4.90e+4 (nM) from 1 assay(s)
BindingDB:  4B7Z IC50: 4.90e+4 (nM) from 1 assay(s)
Binding MOAD:  4B7Z IC50: 4.90e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.307α = 90
b = 111.833β = 90
c = 226.738γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-04
    Type: Initial release
  • Version 1.1: 2013-09-11
    Changes: Database references
  • Version 1.2: 2013-10-30
    Changes: Database references
  • Version 1.3: 2018-01-17
    Changes: Data collection
  • Version 1.4: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Data collection, Derived calculations, Other, Structure summary
  • Version 1.5: 2023-12-20
    Changes: Data collection, Database references, Refinement description, Structure summary