PDBsum entry 2onz

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protein ligands Protein-protein interface(s) links
Transferase PDB id
Jmol PyMol
Protein chain
257 a.a. *
SAH ×2
TMJ ×2
Waters ×105
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of k57a hpnmt with inhibitor 7-(n-4- chlorophenylaminosulfonyl)-thiq and adohcy
Structure: Phenylethanolamine n-methyltransferase. Chain: a, b. Synonym: pnmtase, noradrenaline n-methyltransferase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.80Å     R-factor:   0.216     R-free:   0.264
Authors: N.Drinkwater,J.L.Martin
Key ref: C.L.Gee et al. (2007). Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase. J Med Chem, 50, 4845-4853. PubMed id: 17845018
25-Jan-07     Release date:   09-Oct-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P11086  (PNMT_HUMAN) -  Phenylethanolamine N-methyltransferase
282 a.a.
257 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

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

Dopa Biosynthesis
      Reaction: S-adenosyl-L-methionine + phenylethanolamine = S-adenosyl-L-homocysteine + N-methylphenylethanolamine
+ phenylethanolamine
Bound ligand (Het Group name = SAH)
corresponds exactly
Bound ligand (Het Group name = TMJ)
matches with 45.45% similarity
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     methylation   3 terms 
  Biochemical function     transferase activity     3 terms  


J Med Chem 50:4845-4853 (2007)
PubMed id: 17845018  
Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase.
C.L.Gee, N.Drinkwater, J.D.Tyndall, G.L.Grunewald, Q.Wu, M.J.McLeish, J.L.Martin.
Shape complementarity is a fundamental principle of inhibitor design. Here we show that an enzyme for which the crystal structure has been determined (phenylethanolamine N-methyltransferase, PNMT) conceals a cryptic binding site. This site is revealed upon binding of inhibitors that are double the size of the physiological substrate. These large inhibitors are not predicted to bind in that they protrude through the accessible surface calculated from a PNMT/7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) crystal structure, yet they are potent inhibitors of PNMT. We determined structures of the enzyme complexed with large inhibitors and found that the volume of the active site increases by 140 A3 upon binding. Changes in active site size and shape are brought about by unfavorable side chain conformations and rigid body helix motions. The energetic cost is modest, estimated at 2-3 kcal/mol from mutational analyses. Our findings further underline the importance of protein flexibility in structure-based inhibitor design studies.

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
19570037 N.Drinkwater, C.L.Gee, M.Puri, K.R.Criscione, M.J.McLeish, G.L.Grunewald, and J.L.Martin (2009).
Molecular recognition of physiological substrate noradrenaline by the adrenaline-synthesizing enzyme PNMT and factors influencing its methyltransferase activity.
  Biochem J, 422, 463-471.
PDB codes: 3hca 3hcb 3hcc 3hcd 3hce 3hcf
19733262 P.Georgieva, Q.Wu, M.J.McLeish, and F.Himo (2009).
The reaction mechanism of phenylethanolamine N-methyltransferase: a density functional theory study.
  Biochim Biophys Acta, 1794, 1831-1837.  
18024134 G.L.Grunewald, M.R.Seim, S.R.Bhat, M.E.Wilson, and K.R.Criscione (2008).
Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase.
  Bioorg Med Chem, 16, 542-559.  
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.