title: Harnessing the evolvability of tricyclic microviridins to dissect protease-inhibitor interactions.
abstract: Understanding and controlling proteolysis is an important goal in therapeutic chemistry. Among the natural products specifically inhibiting proteases microviridins are particularly noteworthy. Microviridins are ribosomally produced and posttranslationally modified peptides that are processed into a unique, cagelike architecture. Here, we report a combined rational and random mutagenesis approach that provides fundamental insights into selectivity-conferring moieties of microviridins. The potent variant microviridin J was co-crystallized with trypsin, and for the first time the three-dimensional structure of microviridins was determined and the mode of inhibition revealed.
authors.affiliation: Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Strasse 24-25, 14476 Potsdam-Golm (Germany).
authors.forename: Annika R
authors.initials: AR
authors.lastname: Weiz
authors.forename: Keishi
authors.initials: K
authors.lastname: Ishida
authors.forename: Felix
authors.initials: F
authors.lastname: Quitterer
authors.forename: Sabine
authors.initials: S
authors.lastname: Meyer
authors.forename: Jan-Christoph
authors.initials: JC
authors.lastname: Kehr
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Müller
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Christian
authors.initials: C
authors.lastname: Hertweck
authors.forename: Elke
authors.initials: E
authors.lastname: Dittmann
mesh_terms: D001688:Biological Products / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*
chemical_list: D001688:Biological Products; D010455:Peptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; C480589:microviridin J
keywords: RiPPs; cyanobacteria; peptide engineering; protease inhibitors; structure elucidation