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PDBsum entry 3hcc

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protein ligands Protein-protein interface(s) links
Transferase PDB id
3hcc
Jmol
Contents
Protein chain
259 a.a. *
Ligands
LT3 ×2
SAH ×2
Waters ×269
* Residue conservation analysis
PDB id:
3hcc
Name: Transferase
Title: Crystal structure of hpnmt in complex with anti-9-amino-5- (trifluromethyl) benzonorbornene and adohcy
Structure: Phenylethanolamine n-methyltransferase. Chain: a, b. Synonym: pnmtase, noradrenaline n-methyltransferase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pnmt, pent. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.30Å     R-factor:   0.208     R-free:   0.240
Authors: N.Drinkwater,J.L.Martin,C.L.Gee,M.Puri
Key ref: N.Drinkwater et al. (2009). Molecular recognition of physiological substrate noradrenaline by the adrenaline-synthesizing enzyme PNMT and factors influencing its methyltransferase activity. Biochem J, 422, 463-471. PubMed id: 19570037
Date:
06-May-09     Release date:   25-Aug-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P11086  (PNMT_HUMAN) -  Phenylethanolamine N-methyltransferase
Seq:
Struc:
282 a.a.
259 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.1.1.28  - Phenylethanolamine N-methyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Dopa Biosynthesis
      Reaction: S-adenosyl-L-methionine + phenylethanolamine = S-adenosyl-L-homocysteine + N-methylphenylethanolamine
S-adenosyl-L-methionine
+
phenylethanolamine
Bound ligand (Het Group name = LT3)
matches with 52.00% similarity
=
S-adenosyl-L-homocysteine
Bound ligand (Het Group name = SAH)
corresponds exactly
+ N-methylphenylethanolamine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytosol   1 term 
  Biological process     small molecule metabolic process   5 terms 
  Biochemical function     transferase activity     3 terms  

 

 
    reference    
 
 
Biochem J 422:463-471 (2009)
PubMed id: 19570037  
 
 
Molecular recognition of physiological substrate noradrenaline by the adrenaline-synthesizing enzyme PNMT and factors influencing its methyltransferase activity.
N.Drinkwater, C.L.Gee, M.Puri, K.R.Criscione, M.J.McLeish, G.L.Grunewald, J.L.Martin.
 
  ABSTRACT  
 
Substrate specificity is critically important for enzyme catalysis. In the adrenaline-synthesizing enzyme PNMT (phenylethanolamine N-methyltransferase), minor changes in substituents can convert substrates into inhibitors. Here we report the crystal structures of six human PNMT complexes, including the first structure of the enzyme in complex with its physiological ligand R-noradrenaline. Determining this structure required rapid soak methods because of the tendency for noradrenaline to oxidize. Comparison of the PNMT-noradrenaline complex with the previously determined PNMT-p-octopamine complex demonstrates that these two substrates form almost equivalent interactions with the enzyme and show that p-octopamine is a valid model substrate for PNMT. The crystal structures illustrate the adaptability of the PNMT substrate binding site in accepting multi-fused ring systems, such as substituted norbornene, as well as noradrenochrome, the oxidation product of noradrenaline. These results explain why only a subset of ligands recognized by PNMT are methylated by the enzyme; bulky substituents dictate the binding orientation of the ligand and can thereby place the acceptor amine too far from the donor methyl group for methylation to occur. We also show how the critical Glu(185) catalytic residue can be replaced by aspartic acid with a loss of only 10-fold in catalytic efficiency. This is because protein backbone movements place the Asp(185) carboxylate almost coincident with the carboxylate of Glu(185). Conversely, replacement of Glu(185) by glutamine reduces catalytic efficiency almost 300-fold, not only because of the loss of charge, but also because the variant residue does not adopt the same conformation as Glu(185).
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21053051 A.K.Malde, and A.E.Mark (2011).
Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes.
  J Comput Aided Mol Des, 25, 1.  
20642456 N.Drinkwater, H.Vu, K.M.Lovell, K.R.Criscione, B.M.Collins, T.E.Prisinzano, S.A.Poulsen, M.J.McLeish, G.L.Grunewald, and J.L.Martin (2010).
Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors.
  Biochem J, 431, 51-61.
PDB codes: 3kpj 3kpu 3kpv 3kpw 3kpy 3kqm 3kqo 3kqp 3kqq 3kqs 3kqt 3kqv 3kqw 3kqy 3kr0 3kr1 3kr2
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