1. Molecular recognition of sub-micromolar inhibitors by the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase.
- Author
-
McMillan FM, Archbold J, McLeish MJ, Caine JM, Criscione KR, Grunewald GL, and Martin JL
- Subjects
- Benzazepines chemistry, Binding Sites, Crystallography, X-Ray, Humans, Isoquinolines chemistry, Models, Molecular, Phenylethanolamine N-Methyltransferase chemistry, Phenylethanolamine N-Methyltransferase metabolism, Protein Binding, Quinolines chemistry, S-Adenosylhomocysteine chemistry, Substrate Specificity, Epinephrine biosynthesis, Phenylethanolamine N-Methyltransferase antagonists & inhibitors
- 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 beta-hydroxyl of norepinephrine rather than the amine. These studies provide further clues for the development of improved inhibitors for use as pharmacological probes.
- Published
- 2004
- Full Text
- View/download PDF