McMahon SA

References (2)

Title : Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates - Czekster_2017_Nat.Commun_8_1045
Author(s) : Czekster CM , Ludewig H , McMahon SA , Naismith JH
Ref : Nat Commun , 8 :1045 , 2017
Abstract : 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.
ESTHER : Czekster_2017_Nat.Commun_8_1045
PubMedSearch : Czekster_2017_Nat.Commun_8_1045
PubMedID: 29051530
Gene_locus related to this paper: 9agar-h2e7q8

Title : The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery. - Moynie_2013_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_69_25
Author(s) : Moynie L , Schnell R , McMahon SA , Sandalova T , Boulkerou WA , Schmidberger JW , Alphey M , Cukier C , Duthie F , Kopec J , Liu H , Jacewicz A , Hunter WN , Naismith JH , Schneider G
Ref : Acta Crystallographica Sect F Struct Biol Cryst Commun , 69 :25 , 2013
Abstract : Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.
ESTHER : Moynie_2013_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_69_25
PubMedSearch : Moynie_2013_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_69_25
PubMedID: 23295481
Gene_locus related to this paper: pseae-PA2086