1YZ3

Structure of human pnmt complexed with cofactor product adohcy and inhibitor SK&F 64139

Summary for 1YZ3

• Entry DOI: 10.2210/pdb1yz3/pdb
• Related: 1HNN 1N7I 1N7J
• Descriptor: Phenylethanolamine N-methyltransferase, 7,8-DICHLORO-1,2,3,4-TETRAHYDROISOQUINOLINE, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: enzyme, product, inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 64864.92

Authors

Wu, Q.,Gee, C.L.,Lin, F.,Martin, J.L.,Grunewald, G.L.,McLeish, M.J. (deposition date: 2005-02-27, release date: 2006-02-07, Last modification date: 2023-10-25)

Primary citation

Wu, Q.,Gee, C.L.,Lin, F.,Tyndall, J.D.,Martin, J.L.,Grunewald, G.L.,McLeish, M.J.
Structural, mutagenic, and kinetic analysis of the binding of substrates and inhibitors of human phenylethanolamine N-methyltransferase
J.Med.Chem., 48:7243-7252, 2005

PubMed Abstract: The X-ray structure of human phenylethanolamine N-methyltransferase (hPNMT) complexed with its product, S-adenosyl-L-homocysteine (4), and the most potent inhibitor reported to date, SK&F 64139 (7), was used to identify the residues involved in inhibitor binding. Four of these residues, Val53, Lys57, Glu219 and Asp267, were replaced, in turn, with alanine. All variants had increased Km values for phenylethanolamine (10), but only D267A showed a noteworthy (20-fold) decrease in its kcat value. Both WT hPNMT and D267A had similar kcat values for a rigid analogue, anti-9-amino-6-(trifluoromethyl)benzonorbornene (12), suggesting that Asp267 plays an important role in positioning the substrate but does not participate directly in catalysis. The Ki values for the binding of inhibitors such as 7 to the E219A and D267A variants increased by 2-3 orders of magnitude. Further, the inhibitors were shown to bind up to 50-fold more tightly in the presence of S-adenosyl-L-methionine (3), suggesting that the binding of the latter brings about a conformational change in the enzyme.

PubMed: 16279783
DOI: 10.1021/jm050568o

Experimental method

X-RAY DIFFRACTION (2.4 Å)