5n4e

Prolyl oligopeptidase B from Galerina marginata bound to 35mer hydrolysis and macrocyclization substrate - H698A mutant

spinqualitylabelsall models 5n4e, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5n4e is a 4 chain structure with sequence from Galerina marginata. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function POPB_GALM3 Dual function macrocyclase-peptidase involved in the biosynthesis of the highly toxic amanitin toxin family of macrocycles (PubMed:22202811, PubMed:28866879, PubMed:29051530). Cleaves peptide bonds on the C-terminal side of prolyl residues (PubMed:29051530). The enzyme first removes 10 residues from the N-terminus of a 35-residue substrate (PubMed:29051530). Conformational trapping of the 25 amino-acid peptide forces the enzyme to release this intermediate rather than proceed to macrocyclization (PubMed:29051530). The enzyme rebinds the 25 amino-acid peptide in a different conformation and catalyzes macrocyclization of the N-terminal eight residues (PubMed:28866879, PubMed:29051530). Publication Abstract from PubMed Peptide macrocycles are promising therapeutic molecules because they are protease resistant, structurally rigid, membrane permeable, and capable of modulating protein-protein interactions. Here, we report the characterization of the dual function macrocyclase-peptidase enzyme involved in the biosynthesis of the highly toxic amanitin toxin family of macrocycles. The enzyme first removes 10 residues from the N-terminus of a 35-residue substrate. Conformational trapping of the 25 amino-acid peptide forces the enzyme to release this intermediate rather than proceed to macrocyclization. The enzyme rebinds the 25 amino-acid peptide in a different conformation and catalyzes macrocyclization of the N-terminal eight residues. Structures of the enzyme bound to both substrates and biophysical analysis characterize the different binding modes rationalizing the mechanism. Using these insights simpler substrates with only five C-terminal residues were designed, allowing the enzyme to be more effectively exploited in biotechnology. Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates.,Czekster CM, Ludewig H, McMahon SA, Naismith JH Nat Commun. 2017 Oct 19;8(1):1045. doi: 10.1038/s41467-017-00862-4. PMID:29051530 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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