title: Structural basis of lantibiotic recognition by the nisin resistance protein from Streptococcus agalactiae.
abstract: Lantibiotics are potent antimicrobial peptides. Nisin is the most prominent member and contains five crucial lanthionine rings. Some clinically relevant bacteria express membrane-associated resistance proteins that proteolytically inactivate nisin. However, substrate recognition and specificity of these proteins is unknown. Here, we report the first three-dimensional structure of a nisin resistance protein from Streptococcus agalactiae (SaNSR) at 2.2 Å resolution. It contains an N-terminal helical bundle, and protease cap and core domains. The latter harbors the highly conserved TASSAEM region, which lies in a hydrophobic tunnel formed by all domains. By integrative modeling, mutagenesis studies, and genetic engineering of nisin variants, a model of the SaNSR/nisin complex is generated, revealing that SaNSR recognizes the last C-terminally located lanthionine ring of nisin. This determines the substrate specificity of SaNSR and ensures the exact coordination of the nisin cleavage site at the TASSAEM region.
authors.affiliation: Institute of Biochemistry, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Khosa
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Frieg
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mulnaes
authors.affiliation: Protein Production Facility, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Kleinschrodt
authors.affiliation: Crystal and X-ray Facility, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Hoeppner
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
authors.affiliation: Institute of Biochemistry, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Sander H J
authors.initials: SH
authors.lastname: Smits
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001430:Bacteriocins / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D024881:Drug Resistance, Bacterial; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009561:Nisin / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D013292:Streptococcus agalactiae / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D001430:Bacteriocins; D009561:Nisin