3S68

Rat COMT in complex with SAM and Tolcapone at 1.85A, P3221, Rfree=22.0


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors

Ellermann, M.Lerner, C.Burgy, G.Ehler, A.Bissantz, C.Jakob-Roetne, R.Paulini, R.Allemann, O.Tissot, H.Grunstein, D.Stihle, M.Diederich, F.Rudolph, M.G.

(2012) Acta Crystallogr D Biol Crystallogr 68: 253-260

  • DOI: https://doi.org/10.1107/S0907444912001138
  • Primary Citation of Related Structures:  
    3NWB, 3NWE, 3R6T, 3S68, 3U81

  • PubMed Abstract: 

    The biological activity of catechol neurotransmitters such as dopamine in the synapse is modulated by transporters and enzymes. Catechol-O-methyltransferase (COMT; EC 2.1.1.6) inactivates neurotransmitters by catalyzing the transfer of a methyl group from S-adenosylmethionine to catechols in the presence of Mg²⁺. This pathway also inactivates L-DOPA, the standard therapeutic for Parkinson's disease. Depletion of catechol neurotransmitters in the prefrontal cortex has been linked to schizophrenia. The inhibition of COMT therefore promises improvements in the treatment of these diseases. The concept of bisubstrate inhibitors for COMT has been described previously. Here, ribose-modified bisubstrate inhibitors were studied. Three high-resolution crystal structures of COMT in complex with novel ribose-modified bisubstrate inhibitors confirmed the predicted binding mode but displayed subtle alterations at the ribose-binding site. The high affinity of the inhibitors can be convincingly rationalized from the structures, which document the possibility of removing and/or replacing the ribose 3'-hydroxyl group and provide a framework for further inhibitor design.


  • Organizational Affiliation

    Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, CH-8093 Zürich, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Catechol O-methyltransferase221Rattus norvegicusMutation(s): 0 
Gene Names: Comt
EC: 2.1.1.6
UniProt
Find proteins for P22734 (Rattus norvegicus)
Explore P22734 
Go to UniProtKB:  P22734
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22734
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SAM
Query on SAM

Download Ideal Coordinates CCD File 
H [auth A]S-ADENOSYLMETHIONINE
C15 H22 N6 O5 S
MEFKEPWMEQBLKI-FCKMPRQPSA-N
TCW
Query on TCW

Download Ideal Coordinates CCD File 
G [auth A]Tolcapone
C14 H11 N O5
MIQPIUSUKVNLNT-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
B [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
TCW BindingDB:  3S68 IC50: min: 0.91, max: 2200 (nM) from 6 assay(s)
PDBBind:  3S68 IC50: 2.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.604α = 90
b = 50.604β = 90
c = 168.584γ = 120
Software Package:
Software NamePurpose
PHASERphasing
PHENIXrefinement
XDSdata reduction
SADABSdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-01
    Type: Initial release
  • Version 1.1: 2012-02-22
    Changes: Database references
  • Version 1.2: 2012-04-11
    Changes: Database references
  • Version 1.3: 2012-05-23
    Changes: Structure summary
  • Version 1.4: 2017-11-08
    Changes: Refinement description
  • Version 1.5: 2024-03-20
    Changes: Data collection, Database references, Derived calculations