1yz3
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Structure of human pnmt complexed with cofactor product adohcy and inhibitor SK&F 64139
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Hypertension, essential, 145500 (1) OMIM:[171190]
About this StructureAbout this Structure
1YZ3 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 Full crystallographic information is available from OCA.
ReferenceReference
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 Thu Feb 21 16:10:34 2008