RCSB PDB - 1MX1: Crystal Structure of Human Liver Carboxylesterase in complex with tacrine

 1MX1

Crystal Structure of Human Liver Carboxylesterase in complex with tacrine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.162 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Crystal Structure of Human Carboxylesterase 1 Complexed with the Alzheimer's Drug Tacrine: From Binding Promiscuity to Selective Inhibition

Bencharit, S.Morton, C.L.Hyatt, J.L.Kuhn, P.Danks, M.K.Potter, P.M.Redinbo, M.R.

(2003) Chem Biol 10: 341-349

  • DOI: https://doi.org/10.1016/s1074-5521(03)00071-1
  • Primary Citation of Related Structures:  
    1MX1

  • PubMed Abstract: 

    Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that plays important roles in narcotic metabolism, clinical prodrug activation, and the processing of fatty acid and cholesterol derivatives. We determined the 2.4 A crystal structure of hCE1 in complex with tacrine, the first drug approved for treating Alzheimer's disease, and compare this structure to the Torpedo californica acetylcholinesterase (AcChE)-tacrine complex. Tacrine binds in multiple orientations within the catalytic gorge of hCE1, while it stacks in the smaller AcChE active site between aromatic side chains. Our results show that hCE1's promiscuous action on distinct substrates is enhanced by its ability to interact with ligands in multiple orientations at once. Further, we use our structure to identify tacrine derivatives that act as low-micromolar inhibitors of hCE1 and may provide new avenues for treating narcotic abuse and cholesterol-related diseases.


  • Organizational Affiliation

    Department of Chemistry, School of Dentistry, University of North Carolina, Chapel Hill, 27599, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
liver Carboxylesterase I
A, B, C, D, E
548Homo sapiensMutation(s): 0 
EC: 3.1.1.1 (PDB Primary Data), 3.1.1.56 (UniProt), 3.1.1.13 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P23141 (Homo sapiens)
Explore P23141 
Go to UniProtKB:  P23141
PHAROS:  P23141
GTEx:  ENSG00000198848 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23141
Glycosylation
Glycosylation Sites: 1Go to GlyGen: P23141-1
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-alpha-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
G
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G07375KG
GlyCosmos:  G07375KG
GlyGen:  G07375KG
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SIA
Query on SIA

Download Ideal Coordinates CCD File 
I [auth A],
L [auth B],
P [auth D],
S [auth E]
N-acetyl-alpha-neuraminic acid
C11 H19 N O9
SQVRNKJHWKZAKO-YRMXFSIDSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
H [auth A]
K [auth B]
O [auth D]
R [auth E]
U [auth F]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
THA
Query on THA

Download Ideal Coordinates CCD File 
J [auth A]
M [auth B]
N [auth C]
Q [auth D]
T [auth E]
TACRINE
C13 H14 N2
YLJREFDVOIBQDA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
THA BindingDB:  1MX1 Ki: 1.00e+5 (nM) from 1 assay(s)
IC50: 1.00e+5 (nM) from 1 assay(s)
PDBBind:  1MX1 Ki: 1.00e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.162 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.021α = 90
b = 117.03β = 95.69
c = 176.01γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-22
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Structure summary