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PDBsum entry 2cl5

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2cl5
Jmol
Contents
Protein chains
215 a.a. *
Ligands
SAM ×2
BIE ×2
BU3 ×3
MES
Metals
_MG ×2
Waters ×554
* Residue conservation analysis
PDB id:
2cl5
Name: Transferase
Title: Catechol-o-methyltransferase in complex with an inhibitor
Structure: Catechol o-methyltransferase. Chain: a, b. Engineered: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.6Å     R-factor:   0.151     R-free:   0.178
Authors: P.N.Palma,M.L.Rodrigues,M.Archer,M.J.Bonifacio,A.I.Loureiro, D.A.Learmonth,M.A.Carrondo,P.Soares-Da-Silva
Key ref: P.N.Palma et al. (2006). Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation. Mol Pharmacol, 70, 143-153. PubMed id: 16618795 DOI: 10.1124/mol.106.023119
Date:
26-Apr-06     Release date:   28-Jun-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P22734  (COMT_RAT) -  Catechol O-methyltransferase
Seq:
Struc:
264 a.a.
215 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.1.1.6  - Catechol O-methyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: S-adenosyl-L-methionine + a catechol = S-adenosyl-L-homocysteine + a guaiacol
S-adenosyl-L-methionine
Bound ligand (Het Group name = SAM)
corresponds exactly
+
catechol
Bound ligand (Het Group name = BIE)
matches with 42.00% similarity
= S-adenosyl-L-homocysteine
+ guaiacol
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     neurotransmitter catabolic process   2 terms 
  Biochemical function     magnesium ion binding     3 terms  

 

 
    reference    
 
 
DOI no: 10.1124/mol.106.023119 Mol Pharmacol 70:143-153 (2006)
PubMed id: 16618795  
 
 
Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation.
P.N.Palma, M.L.Rodrigues, M.Archer, M.J.Bonifácio, A.I.Loureiro, D.A.Learmonth, M.A.Carrondo, P.Soares-da-Silva.
 
  ABSTRACT  
 
In this work, we present a comparative case study of "ortho-" and "meta-nitrated" catecholic inhibitors of catechol-O-methyltransferase (COMT), with regard to their interaction with the catalytic site of the enzyme and the in vitro regioselective formation of their mono-O-methyl ether metabolites. In particular, the effects of altering the attachment position of the inhibitors' side-chain substituent, within the classic nitrocatechol pharmacophore, were investigated. For this purpose, we compared two simple regioisomeric nitrocatechol-type inhibitors of COMT, BIA 3-228 and BIA 8-176, which contain the benzoyl substituent attached at the meta and ortho positions, respectively, relative to the nitro group. The two compounds were slowly O-methylated by COMT in vitro, but the particular substitution pattern of each compound was shown to have a profound impact on the regioselectivity of their O-methylation. To provide a plausible interpretation of these results, a comprehensive analysis of the protein-inhibitor interactions and of the relative chemical susceptibility to O-methylation of the catechol hydroxyl groups was performed by means of docking simulations and ab initio molecular orbital calculations. The major structural and chemical factors that determine the enzyme regioselectivity of O-methylation were identified, and the X-ray structure of the complex of COMT with S-adenosyl-l-methionine and BIA 8-176 is herein disclosed. This is the first reported structure of the soluble form of COMT complexed with a nitrocatecholic inhibitor having a bulky substituent group in adjacent position (ortho) to the nitro group. Structural and dynamic aspects of this complex are analyzed and discussed, in the context of the present study.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19857499 I.Gómez García, C.E.Stevenson, I.Usón, C.L.Freel Meyers, C.T.Walsh, and D.M.Lawson (2010).
The crystal structure of the novobiocin biosynthetic enzyme NovP: the first representative structure for the TylF O-methyltransferase superfamily.
  J Mol Biol, 395, 390-407.
PDB code: 2wk1
18502766 S.Singh, J.G.McCoy, C.Zhang, C.A.Bingman, G.N.Phillips, and J.S.Thorson (2008).
Structure and mechanism of the rebeccamycin sugar 4'-O-methyltransferase RebM.
  J Biol Chem, 283, 22628-22636.
PDB code: 3bus
17894650 M.J.Bonifácio, P.N.Palma, L.Almeida, and P.Soares-da-Silva (2007).
Catechol-O-methyltransferase and its inhibitors in Parkinson's disease.
  CNS Drug Rev, 13, 352-379.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.