5kok

Pavine N-methyltransferase in complex with Tetrahydropapaverine and S-adenosylhomocysteine pH 7.25

spinqualitylabelsall models 5kok, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5kok is a 2 chain structure with sequence from Thalictrum flavum subsp. glaucum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.792Å Ligands: R9T, S9T, SAH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PNMT_THLFG Publication Abstract from PubMed Benzylisoquinoline alkaloids (BIAs) are produced in a wide variety of plants and include many common analgesic, antitussive and anticancer compounds. Several members of a distinct family of S-adenosylmethionine (SAM)-dependent N-methyltransferases (NMTs) play critical roles BIA biosynthesis, but, the molecular basis of substrate recognition and catalysis are not known for NMTs involved in BIA metabolism. To address this issue, the crystal structure of pavine NMT (PavNMT) from Thalictrum flavum was solved using selenomethionine-substituted protein (dmin = 2.8 A). Additional structures were determined for the native protein (dmin = 2.0 A), as well as binary complexes with SAM (dmin = 2.3 A) or the reaction product S-adenosylhomocysteine (SAH) (dmin = 1.6 A). The structure of a complex with SAH and two molecules of tetrahydropapaverine (THP, one as the S conformer and a second in the R configuration) (dmin = 1.8 A) revealed key features of substrate recognition. PavNMT converted racemic THP to laudanosine, but the enzyme showed a preference for (+/-)-pavine and (S)-reticuline as substrates. These structures suggest the involvement of highly conserved residues at the active site. Mutagenesis of three residues near the methyl group of SAM and the nitrogen atom of the alkaloid acceptor decreased enzyme activity without disrupting the structure of the protein. The binding site for THP provides a framework for understanding substrate specificity amongst numerous NMTs involved in the biosynthesis of BIAs and other specialized metabolites. This information will facilitate metabolic engineering efforts aimed at producing medicinally important compounds in heterologous systems such as yeast. Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism.,Torres MA, Hoffarth E, Eugenio L, Savtchouk J, Chen X, Morris J, Facchini PJ, Ng KK J Biol Chem. 2016 Aug 29. pii: jbc.M116.747261. PMID:27573242 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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