RCSB PDB - 5K0L: Crystal Structure of COMT in complex with 5-[5-[1-(4-methoxyphenyl)cyclopropyl]-1H-pyrazol-3-yl]-2,4-dimethyl-1,3-thiazole

 5K0L

Crystal Structure of COMT in complex with 5-[5-[1-(4-methoxyphenyl)cyclopropyl]-1H-pyrazol-3-yl]-2,4-dimethyl-1,3-thiazole


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 6P2Click on this verticalbar to view details

This is version 1.4 of the entry. See complete history


Literature

Design of Potent and Druglike Nonphenolic Inhibitors for Catechol O-Methyltransferase Derived from a Fragment Screening Approach Targeting the S-Adenosyl-l-methionine Pocket.

Lerner, C.Jakob-Roetne, R.Buettelmann, B.Ehler, A.Rudolph, M.Rodriguez Sarmiento, R.M.

(2016) J Med Chem 59: 10163-10175

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00927
  • Primary Citation of Related Structures:  
    5K03, 5K05, 5K09, 5K0B, 5K0C, 5K0F, 5K0G, 5K0J, 5K0L, 5K0N

  • PubMed Abstract: 

    A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia.


  • Organizational Affiliation

    Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Catechol O-methyltransferase
A, B, C, D
219Rattus norvegicusMutation(s): 2 
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
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6P2
Query on 6P2

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
N [auth C],
S [auth D]
5-{3-[1-(4-methoxyphenyl)cyclopropyl]-1H-pyrazol-5-yl}-2,4-dimethyl-1,3-thiazole
C18 H19 N3 O S
ONGUVGXZNLWDHM-UHFFFAOYSA-N
NHE
Query on NHE

Download Ideal Coordinates CCD File 
G [auth A]
K [auth B]
O [auth C]
P [auth C]
T [auth D]
2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID
C8 H17 N O3 S
MKWKNSIESPFAQN-UHFFFAOYSA-N
K
Query on K

Download Ideal Coordinates CCD File 
H [auth A],
L [auth B],
Q [auth C],
V [auth D]
POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
M [auth C],
R [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.167α = 90
b = 69.963β = 94.18
c = 104.053γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PDB_EXTRACTdata extraction
PHENIXrefinement
XDSdata reduction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 6P2Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-07
    Type: Initial release
  • Version 1.1: 2016-10-12
    Changes: Database references
  • Version 1.2: 2016-12-21
    Changes: Database references
  • Version 1.3: 2019-06-12
    Changes: Data collection, Structure summary
  • Version 1.4: 2024-05-08
    Changes: Data collection, Database references, Derived calculations