spacer
spacer

PDBsum entry 1h1d

Go to PDB code: 
protein ligands metals links
Transferase PDB id
1h1d
Jmol
Contents
Protein chain
214 a.a. *
Ligands
SAM
BIA
Metals
_MG
Waters ×93
* Residue conservation analysis
PDB id:
1h1d
Name: Transferase
Title: Catechol o-methyltransferase
Structure: Catechol-o-methyltransferase. Chain: a. Fragment: soluble form, residues 44-264. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Tissue: liver. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: gold.
Resolution:
2.00Å     R-factor:   0.174     R-free:   0.198
Authors: M.Archer,M.L.Rodrigues,P.M.Matias,M.J.Bonifacio, D.A.Learmonth,P.Soares-Da-Silva,M.A.Carrondo
Key ref: M.J.Bonifácio et al. (2002). Kinetics and crystal structure of catechol-o-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application. Mol Pharmacol, 62, 795-805. PubMed id: 12237326
Date:
12-Jul-02     Release date:   17-Jul-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P22734  (COMT_RAT) -  Catechol O-methyltransferase
Seq:
Struc:
264 a.a.
214 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
= 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    
 
 
Mol Pharmacol 62:795-805 (2002)
PubMed id: 12237326  
 
 
Kinetics and crystal structure of catechol-o-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application.
M.J.Bonifácio, M.Archer, M.L.Rodrigues, P.M.Matias, D.A.Learmonth, M.A.Carrondo, P.Soares-Da-Silva.
 
  ABSTRACT  
 
Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics. In particular, inactivation of drugs such as L-3,4-dihydroxyphenylalanine (L-DOPA) via O-methylation is of relevant pharmacological importance, because L-DOPA is currently the most effective drug used in the treatment of Parkinson's disease. This justified the interest in developing COMT inhibitors as potential adjuncts to L-DOPA therapy. The kinetics of inhibition by BIA 3-335 (1-[3,4-dihydroxy-5-nitrophenyl]-3-(N-3'-trifluormethylphenyl)-piperazine-1-propanone dihydrochloride) were characterized using recombinant rat soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K(i) of 6.0 +/- 1.6 nM and displaying a competitive inhibition toward the substrate binding site and uncompetitive inhibition toward the S-adenosyl-L-methionine (SAM) binding site. The 2.0-A resolution crystal structure of COMT in complex with its cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic interactions between the important residues at the active site and the inhibitor. This is the first report of a three-dimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19718498 H.Venselaar, R.P.Joosten, B.Vroling, C.A.Baakman, M.L.Hekkelman, E.Krieger, and G.Vriend (2010).
Homology modelling and spectroscopy, a never-ending love story.
  Eur Biophys J, 39, 551-563.  
18953341 Z.M.Ahmed, S.Masmoudi, E.Kalay, I.A.Belyantseva, M.A.Mosrati, R.W.Collin, S.Riazuddin, M.Hmani-Aifa, H.Venselaar, M.N.Kawar, A.Tlili, B.van der Zwaag, S.Y.Khan, L.Ayadi, S.A.Riazuddin, R.J.Morell, A.J.Griffith, I.Charfedine, R.Caylan, J.Oostrik, A.Karaguzel, A.Ghorbel, S.Riazuddin, T.B.Friedman, H.Ayadi, and H.Kremer (2008).
Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans.
  Nat Genet, 40, 1335-1340.  
17294500 L.A.Passarinha, M.J.Bonifácio, and J.A.Queiroz (2007).
Comparative study on the interaction of recombinant human soluble catechol-O-methyltransferase on some hydrophobic adsorbents.
  Biomed Chromatogr, 21, 430-438.  
17660248 M.Graña, A.Haouz, A.Buschiazzo, I.Miras, A.Wehenkel, V.Bondet, W.Shepard, F.Schaeffer, S.T.Cole, and P.M.Alzari (2007).
The crystal structure of M. leprae ML2640c defines a large family of putative S-adenosylmethionine-dependent methyltransferases in mycobacteria.
  Protein Sci, 16, 1896-1904.
PDB codes: 2ckd 2uyo 2uyq
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.  
16892369 R.Paulini, C.Trindler, C.Lerner, L.Brändli, W.B.Schweizer, R.Jakob-Roetne, G.Zürcher, E.Borroni, and F.Diederich (2006).
Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity.
  ChemMedChem, 1, 340-357.  
  16508109 M.L.Rodrigues, M.J.Bonifácio, P.Soares-da-Silva, M.A.Carrondo, and M.Archer (2005).
Crystallization and preliminary X-ray diffraction studies of a catechol-O-methyltransferase/inhibitor complex.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 118-120.  
15368579 R.Paulini, C.Lerner, R.Jakob-Roetne, G.Zürcher, E.Borroni, and F.Diederich (2004).
Bisubstrate inhibitors of the enzyme catechol O-methyltransferase (COMT): efficient inhibition despite the lack of a nitro group.
  Chembiochem, 5, 1270-1274.  
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 codes are shown on the right.