6ws1 | pdb_00006ws1

Crystal structure of human phenylethanolamine N-methyltransferase (PNMT) in complex with (2S)-2-amino-4-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-(7,8-dichloro-1,2,3,4-tetrahydroisoquinolin-4-yl)propyl)amino)butanoic acid and AdoHcy (SAH)

spinqualitylabelsall models 6ws1, resolution 2.76Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.76Å Ligands: CD, EDO, K, SAH, U87 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Phenylethanolamine N-methyltransferase (PNMT) is a critical enzyme in catecholamine synthesis. It transfers the methyl group of S-adenosylmethionine (SAM) to catalyze the synthesis of epinephrine from norepinephrine. Epinephrine has been associated with diverse human processes, including the regulation of blood pressure and respiration, as well as neurodegeneration found in Alzheimer's disease. Human PNMT (hPNMT) proceeds through an SN2 transition state (TS), in which the transfer of the methyl group is rate-limiting. TS analogue enzyme inhibitors are specific for their target and bind orders of magnitude more tightly than their substrates. Molecules resembling the TS of hPNMT were designed, synthesized, and kinetically characterized. This new inhibitory scaffold was designed to mimic the geometry and electronic properties of the hPNMT TS. Synthetic efforts resulted in a tight-binding inhibitor with a Ki value of 12.0 nM. This is among the first TS analogue inhibitors of methyltransferase enzymes to show an affinity in the nanomolar range. Isothermal titration calorimetry (ITC) measurements indicated negative cooperative binding of inhibitor to the dimeric protein, driven by favorable entropic contributions. Structural analysis revealed that inhibitor 3 binds to hPNMT by filling the catalytic binding pockets for the cofactor (SAM) and the substrate (norepinephrine) binding sites. Transition-State Analogues of Phenylethanolamine N-methyltransferase.,Mahmoodi N, Harijan RK, Schramm VL J Am Chem Soc. 2020 Jul 23. doi: 10.1021/jacs.0c05446. PMID:32702980 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phenylethanolamine N-methyltransferase

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