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Transferase PDB id
2g70
Jmol
Contents
Protein chains
261 a.a. *
Ligands
SAM ×2
HNT ×3
PO4
Waters ×81
* Residue conservation analysis
PDB id:
2g70
Name: Transferase
Title: Structure of human pnmt in complex with inhibitor 3-hydroxym nitro-thiq and adomet (sam)
Structure: Phenylethanolamine n-methyltransferase. Chain: a, b. Synonym: pnmtase, noradrenaline n-methyltransferase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.40Å     R-factor:   0.240     R-free:   0.285
Authors: J.D.A.Tyndall,C.L.Gee,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 DOI: 10.1021/jm0703385
Date:
27-Feb-06     Release date:   13-Feb-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P11086  (PNMT_HUMAN) -  Phenylethanolamine N-methyltransferase
Seq:
Struc: 		282 a.a.
261 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
Bound ligand (Het Group name = SAM)
corresponds exactly 		+ phenylethanolamine
 = S-adenosyl-L-homocysteine
 +
N-methylphenylethanolamine
Bound ligand (Het Group name = HNT)
matches with 62.50% 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     cellular nitrogen compound metabolic process   4 terms 
  Biochemical function     transferase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm0703385 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.
 
  ABSTRACT  
 
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.