1yz3
From Proteopedia
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Structure of human pnmt complexed with cofactor product adohcy and inhibitor SK&F 64139
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Hypertension, essential, 145500 (1) OMIM:[171190]
About this Structure
1YZ3 is a Single protein structure of sequence from Homo sapiens with SKA and SAH as ligands. Active as Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 Full crystallographic information is available from OCA.
Reference
Structural, mutagenic, and kinetic analysis of the binding of substrates and inhibitors of human phenylethanolamine N-methyltransferase., Wu Q, Gee CL, Lin F, Tyndall JD, Martin JL, Grunewald GL, McLeish MJ, J Med Chem. 2005 Nov 17;48(23):7243-52. PMID:16279783
Page seeded by OCA on Mon Nov 12 20:27:02 2007
