3ZV7

Torpedo californica Acetylcholinesterase Inhibition by Bisnorcymserine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.206 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Kinetics of Torpedo Californica Acetylcholinesterase Inhibition by Bisnorcymserine and Crystal Structure of the Complex with its Leaving Group.

Bartolucci, C.Stojan, J.Yu, Q.S.Greig, N.H.Lamba, D.

(2012) Biochem J 444: 269

  • DOI: https://doi.org/10.1042/BJ20111675
  • Primary Citation of Related Structures:  
    3ZV7

  • PubMed Abstract: 

    Natural and synthetic carbamates act as pseudo-irreversible inhibitors of AChE (acetylcholinesterase) as well as BChE (butyrylcholinesterase), two enzymes involved in neuronal function as well as in the development and progression of AD (Alzheimer's disease). The AChE mode of action is characterized by a rapid carbamoylation of the active-site Ser(200) with release of a leaving group followed by a slow regeneration of enzyme action due to subsequent decarbamoylation. The experimental AD therapeutic bisnorcymserine, a synthetic carbamate, shows an interesting activity and selectivity for BChE, and its clinical development is currently being pursued. We undertook detailed kinetic studies on the activity of the carbamate bisnorcymserine with Tc (Torpedo californica) AChE and, on the basis of the results, crystallized the complex between TcAChE and bisnorcymserine. The X-ray crystal structure showed only the leaving group, bisnoreseroline, trapped at the bottom of the aromatic enzyme gorge. Specifically, bisnoreseroline interacts in a non-covalent way with Ser(200) and His(440), disrupting the existing interactions within the catalytic triad, and it stacks with Trp(84) at the bottom of the gorge, giving rise to an unprecedented hydrogen-bonding contact. These interactions point to a dominant reversible inhibition mechanism attributable to the leaving group, bisnoreseroline, as revealed by kinetic analysis.


  • Organizational Affiliation

    Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area della Ricerca di Roma, Monterotondo Scalo, Italy. cecilia.bartolucci@ic.cnr.it


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINESTERASE543Tetronarce 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
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
C [auth A]PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
NAG
Query on NAG

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

Download Ideal Coordinates CCD File 
F [auth A]BIS-NORESEROLINE
C11 H14 N2 O
BLEHTFVVORLVPX-MNOVXSKESA-N
PEG
Query on PEG

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D [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
EDO
Query on EDO

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

Download Ideal Coordinates CCD File 
I [auth A]
J [auth A]
K [auth A]
L [auth A]
M [auth A]
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
S [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
NHG PDBBind:  3ZV7 Ki: 1200 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.26 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.206 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.008α = 90
b = 111.008β = 90
c = 137.387γ = 120
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-23
    Type: Initial release
  • Version 1.1: 2019-01-30
    Changes: Data collection, Experimental preparation, Other
  • Version 1.2: 2019-02-06
    Changes: Data collection, Experimental preparation
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary
  • Version 2.1: 2023-12-20
    Changes: Data collection, Database references, Refinement description, Structure summary