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Molecular Recognition of Sub-micromolar Inhibitors by the Epinephrine-Synthesizing Enzyme Phenylethanolamine N-Methyltransferase

Journal Article


Abstract


  • The crystal structures of human phenylethanolamine N-methyltransferase in complex with S-adenosyl-L-homocysteine (7, AdoHcy) and either 7-iodo-1,2,3,4-tetrahydroisoquinoline (2) or 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (3, LY134046) were determined and compared with the structure of the enzyme complex with 7 and 7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (1, SK&F 29661). The enzyme is able to accommodate a variety of chemically disparate functional groups on the aromatic ring of the inhibitors through adaptation of the binding pocket for this substituent and by subtle adjustments of the orientation of the inhibitors within the relatively planar binding site. In addition, the interactions formed by the amine nitrogen of all three inhibitors reinforce the hypothesis that this functional group mimics the β-hydroxyl of norepinephrine rather than the amine. These studies provide further clues for the development of improved inhibitors for use as pharmacological probes.

UOW Authors


  •   McMillan, Fiona (external author)
  •   Archbold, Julia (external author)
  •   Mcleish, Michael (external author)
  •   Caine, Joanne (external author)
  •   Criscione, Kevin (external author)
  •   Grunewald, Gary (external author)
  •   Martin, Jennifer

Publication Date


  • 2004

Citation


  • McMillan, F. M., Archbold, J., Mcleish, M. J., Caine, J. M., Criscione, K. R., Grunewald, G. L. & Martin, J. L. (2004). Molecular Recognition of Sub-micromolar Inhibitors by the Epinephrine-Synthesizing Enzyme Phenylethanolamine N-Methyltransferase. Journal of Medicinal Chemistry, 47 (1), 37-44.

Scopus Eid


  • 2-s2.0-0347991966

Number Of Pages


  • 7

Start Page


  • 37

End Page


  • 44

Volume


  • 47

Issue


  • 1

Place Of Publication


  • United States

Abstract


  • The crystal structures of human phenylethanolamine N-methyltransferase in complex with S-adenosyl-L-homocysteine (7, AdoHcy) and either 7-iodo-1,2,3,4-tetrahydroisoquinoline (2) or 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (3, LY134046) were determined and compared with the structure of the enzyme complex with 7 and 7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (1, SK&F 29661). The enzyme is able to accommodate a variety of chemically disparate functional groups on the aromatic ring of the inhibitors through adaptation of the binding pocket for this substituent and by subtle adjustments of the orientation of the inhibitors within the relatively planar binding site. In addition, the interactions formed by the amine nitrogen of all three inhibitors reinforce the hypothesis that this functional group mimics the β-hydroxyl of norepinephrine rather than the amine. These studies provide further clues for the development of improved inhibitors for use as pharmacological probes.

UOW Authors


  •   McMillan, Fiona (external author)
  •   Archbold, Julia (external author)
  •   Mcleish, Michael (external author)
  •   Caine, Joanne (external author)
  •   Criscione, Kevin (external author)
  •   Grunewald, Gary (external author)
  •   Martin, Jennifer

Publication Date


  • 2004

Citation


  • McMillan, F. M., Archbold, J., Mcleish, M. J., Caine, J. M., Criscione, K. R., Grunewald, G. L. & Martin, J. L. (2004). Molecular Recognition of Sub-micromolar Inhibitors by the Epinephrine-Synthesizing Enzyme Phenylethanolamine N-Methyltransferase. Journal of Medicinal Chemistry, 47 (1), 37-44.

Scopus Eid


  • 2-s2.0-0347991966

Number Of Pages


  • 7

Start Page


  • 37

End Page


  • 44

Volume


  • 47

Issue


  • 1

Place Of Publication


  • United States