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PDBsum entry 3bwm

Go to PDB code: 
protein ligands metals links
Transferase PDB id
3bwm
Jmol
Contents
Protein chain
214 a.a. *
Ligands
SAM
DNC
Metals
_MG
__K
Waters ×110
* Residue conservation analysis
PDB id:
3bwm
Name: Transferase
Title: Crystal structure of human catechol o-methyltransferase with bound sam and dnc
Structure: Catechol o-methyltransferase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Gene: comt. Expressed in: escherichia coli.
Resolution:
1.98Å     R-factor:   0.177     R-free:   0.225
Authors: K.Rutherford,I.Le Trong,R.E.Stenkamp,W.W.Parson
Key ref:
K.Rutherford et al. (2008). Crystal structures of human 108V and 108M catechol O-methyltransferase. J Mol Biol, 380, 120-130. PubMed id: 18486144 DOI: 10.1016/j.jmb.2008.04.040
Date:
09-Jan-08     Release date:   03-Jun-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P21964  (COMT_HUMAN) -  Catechol O-methyltransferase
Seq:
Struc:
271 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
Bound ligand (Het Group name = DNC)
matches with 57.00% 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: 10.1016/j.jmb.2008.04.040 J Mol Biol 380:120-130 (2008)
PubMed id: 18486144  
 
 
Crystal structures of human 108V and 108M catechol O-methyltransferase.
K.Rutherford, I.Le Trong, R.E.Stenkamp, W.W.Parson.
 
  ABSTRACT  
 
Catechol O-methyltransferase (COMT) plays important roles in the metabolism of catecholamine neurotransmitters and catechol estrogens. The development of COMT inhibitors for use in the treatment of Parkinson's disease has been aided by crystallographic structures of the rat enzyme. However, the human and rat proteins have significantly different substrate specificities. Additionally, human COMT contains a common valine-methionine polymorphism at position 108. The methionine protein is less stable than the valine polymorph, resulting in decreased enzyme activity and protein levels in vivo. Here we describe the crystal structures of the 108V and 108M variants of the soluble form of human COMT bound with S-adenosylmethionine (SAM) and a substrate analog, 3,5-dinitrocatechol. The polymorphic residue 108 is located in the alpha5-beta3 loop, buried in a hydrophobic pocket approximately 16 A from the SAM-binding site. The 108V and 108M structures are very similar overall [RMSD of C(alpha) atoms between two structures (C(alpha) RMSD)=0.2 A], and the active-site residues are superposable, in accord with the observation that SAM stabilizes 108M COMT. However, the methionine side chain is packed more tightly within the polymorphic site and, consequently, interacts more closely with residues A22 (alpha2) and R78 (alpha4) than does valine. These interactions of the larger methionine result in a 0.7-A displacement in the backbone structure near residue 108, which propagates along alpha1 and alpha5 toward the SAM-binding site. Although the overall secondary structures of the human and rat proteins are very similar (C(alpha) RMSD=0.4 A), several nonconserved residues are present in the SAM-(I89M, I91M, C95Y) and catechol- (C173V, R201M, E202K) binding sites. The human protein also contains three additional solvent-exposed cysteine residues (C95, C173, C188) that may contribute to intermolecular disulfide bond formation and protein aggregation.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Crystal structure of human 108V COMT. Ribbon diagrams of human 108V COMT colored from blue (N-terminus) to red (C-terminus) are shown in stereo. SAM (magenta) and DNC (dark blue) are shown in stick representation. K^+ (cyan), Mg^2+ (green), and the side chain of residue V108 (gray) are shown in space-filling representation.
Figure 2.
Fig. 2. SAM-binding site. SAM is shown in stereo with a transparent van der Waals surface and a ball-and-stick representation colored by atom type (C, gray; N, blue; O, red; S, yellow). The side chains of residues that interact with SAM are shown in stick representations with C atoms colored in cyan for 108V COMT, in magenta for 108M COMT, and in salmon for rat COMT (1VID^8) and other atoms colored by atom type as above. The residues that interact with SAM include three nonconserved residues, I89, I91, and C95, of human COMT that replace M89, M91, and Y95 of rat COMT. S119 was omitted for clarity.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 380, 120-130) copyright 2008.  
  Figures were selected by the author.  
 
 
    Author's comment    
 
  Figure 1 above shows the 108V variant of the enzyme (PDB entry 3bwm). For an illustration of the 108M variant (PDB entry 3bwy), see:
    Rutherford K, Alphandéry E, McMillan A, Daggett V, Parson WW (2008). The V108M mutation decreases the structural stability of catechol O-methyltransferase. Biochim Biophys Acta, 17841098-1105. [PubMed id 18474266].

W. Parson
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20382027 K.Rutherford, and V.Daggett (2010).
Polymorphisms and disease: hotspots of inactivation in methyltransferases.
  Trends Biochem Sci, 35, 531-538.  
20399180 M.W.van der Kamp, R.D.Schaeffer, A.L.Jonsson, A.D.Scouras, A.M.Simms, R.D.Toofanny, N.C.Benson, P.C.Anderson, E.D.Merkley, S.Rysavy, D.Bromley, D.A.Beck, and V.Daggett (2010).
Dynameomics: a comprehensive database of protein dynamics.
  Structure, 18, 423-435.  
19435324 K.Rutherford, and V.Daggett (2009).
A hotspot of inactivation: The A22S and V108M polymorphisms individually destabilize the active site structure of catechol O-methyltransferase.
  Biochemistry, 48, 6450-6460.  
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.