1N7J

The structure of Phenylethanolamine N-methyltransferase in complex with S-adenosylhomocysteine and an iodinated inhibitor

Summary for 1N7J

• Entry DOI: 10.2210/pdb1n7j/pdb
• Related: 1HNN
• Descriptor: Phenylethanolamine N-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, 7-IODO-1,2,3,4-TETRAHYDRO-ISOQUINOLINE, ... (4 entities in total)
• Functional Keywords: methyltransferase, catecholamine, adrenaline, epinephrine, s-adenosylmethionine, s-adenolsylhomocysteine, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 63062.96

Authors

McMillan, F.M.,Archbold, J.,McLeish, M.J.,Caine, J.M.,Criscione, K.R.,Grunewald, G.L.,Martin, J.L. (deposition date: 2002-11-15, release date: 2003-12-23, Last modification date: 2024-02-14)

Primary citation

McMillan, F.M.,Archbold, J.,McLeish, M.J.,Caine, J.M.,Criscione, K.R.,Grunewald, G.L.,Martin, J.L.
Molecular recognition of sub-micromolar inhibitors by the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase.
J.Med.Chem., 47:37-44, 2004

PubMed 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.

PubMed: 14695818
DOI: 10.1021/jm0205752

Experimental method

X-RAY DIFFRACTION (2.7 Å)