2WG1

TERNARY COMPLEX OF THE AGED CONJUGATE OF TORPEDO CALIFORNICA ACEYLCHOLINESTERASE WITH SOMAN AND 2-PAM


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.2 of the entry. See complete history


Literature

Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime.

Sanson, B.Nachon, F.Colletier, J.P.Froment, M.T.Toker, L.Greenblatt, H.M.Sussman, J.L.Ashani, Y.Masson, P.Silman, I.Weik, M.

(2009) J Med Chem 52: 7593

  • DOI: https://doi.org/10.1021/jm900433t
  • Primary Citation of Related Structures:  
    2WFZ, 2WG0, 2WG1, 2WG2

  • PubMed Abstract: 

    Organophosphate compounds (OP) are potent inhibitors of acetylcholinesterases (AChEs) and can cause lethal poisoning in humans. Inhibition of AChEs by the OP soman involves phosphonylation of the catalytic serine, and subsequent dealkylation produces a form known as the "aged" enzyme. The nonaged form can be reactivated to a certain extent by nucleophiles, such as pralidoxime (2-PAM), whereas aged forms of OP-inhibited AChEs are totally resistant to reactivation. Here, we solved the X-ray crystal structures of AChE from Torpedo californica (TcAChE) conjugated with soman before and after aging. The absolute configuration of the soman stereoisomer adduct in the nonaged conjugate is P(S)C(R). A structural reorientation of the catalytic His440 side chain was observed during the aging process. Furthermore, the crystal structure of the ternary complex of the aged conjugate with 2-PAM revealed that the orientation of the oxime function does not permit nucleophilic attack on the phosphorus atom, thus providing a plausible explanation for its failure to reactivate the aged soman/AChE conjugate. Together, these three crystal structures provide an experimental basis for the design of new reactivators.


  • Organizational Affiliation

    Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Université Joseph Fourier, 41 Rue Jules Horowitz, 38027 Grenoble, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINESTERASE537Tetronarce californicaMutation(s): 0 
EC: 3.1.1.7
UniProt
Find proteins for P04058 (Tetronarce californica)
Explore P04058 
Go to UniProtKB:  P04058
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04058
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
MES
Query on MES

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth A],
I [auth A]
2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
L [auth A],
M [auth A]
TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
PGE
Query on PGE

Download Ideal Coordinates CCD File 
N [auth A],
O [auth A],
P [auth A]
TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
FP1
Query on FP1

Download Ideal Coordinates CCD File 
E [auth A]N-hydroxy-1-(1-methylpyridin-2(1H)-ylidene)methanamine
C7 H10 N2 O
YDWKOUCMHAMECR-SREVYHEPSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
Q [auth A],
R [auth A],
S [auth A],
T [auth A],
U [auth A]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
GB
Query on GB

Download Ideal Coordinates CCD File 
D [auth A]METHYLPHOSPHONIC ACID ESTER GROUP
C H5 O3 P
YACKEPLHDIMKIO-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.168 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.91α = 90
b = 111.91β = 90
c = 137.17γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata 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: 2009-08-11
    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: 2019-04-03
    Changes: Data collection, Experimental preparation, Other
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary
  • Version 2.1: 2021-05-12
    Changes: Derived calculations, Structure summary
  • Version 2.2: 2023-12-13
    Changes: Data collection, Database references, Refinement description