title: Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis.
abstract: Aminopeptidases are ubiquitous hydrolases that cleave the N-terminal residues of proteins and oligopeptides. They are broadly distributed throughout all kingdoms of life and have been implicated in a wide variety of physiological processes, including viral infection, parasite metabolism, protein processing, regulation of peptide hormones, and cancer cell proliferation. Members of the M1 family, also termed gluzincins, are defined by two highly conserved motifs in the catalytic domain: a zinc-binding motif, HEXXH-(X18)-E; and an exopeptidase motif, GXMEN. We report the high-resolution X-ray structures of E. coli aminopeptidase N (PepN) in complex with three aminobenzosuberone scaffolds that display various Ki values (50, 0.33, and 0.034 µM) and provide a compelling view of the outstanding selectivity of these chemical entities for the M1 aminopeptidases. This series of inhibitors interacts as transition state mimics with highly conserved residues of the catalytic machinery and substrate recognition sites. Structural comparisons and model-building studies allowed a deep interpretation of the SAR observed for bacterial, as well as mammalian enzymes. Proteins 2017; 85:1413-1421. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Paul Scherrer Institut (SLS) WSLB, 5232, Villigen, Suisse, Switzerland.
authors.forename: Guanya
authors.initials: G
authors.lastname: Peng
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: McEwen
authors.affiliation: Paul Scherrer Institut (SLS) WSLB, 5232, Villigen, Suisse, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Olieric
authors.affiliation: Laboratoire de Chimie Organique et Bioorganique, EA4566; Université de Haute Alsace, Institut Jean Baptiste Donnet, Mulhouse, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Laboratoire de Chimie Organique et Bioorganique, EA4566; Université de Haute Alsace, Institut Jean Baptiste Donnet, Mulhouse, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.|Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.|Université de Strasbourg, Illkirch, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Cavarelli
authors.affiliation: Laboratoire de Chimie Organique et Bioorganique, EA4566; Université de Haute Alsace, Institut Jean Baptiste Donnet, Mulhouse, France.
authors.forename: Celine
authors.identifier: http://orcid.org/0000-0003-2257-3865
authors.initials: C
authors.lastname: Tarnus
mesh_terms: D020816:Amino Acid Motifs; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000840:Anisoles / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003508:Cycloheptanes / Q000737:chemistry*; D004851:Epoxide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry* / Q000201:enzymology / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D000840:Anisoles; D001426:Bacterial Proteins; D003508:Cycloheptanes; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C558240:amino-benzosuberone; C075633:pepN protein, Bacteria; D004851:Epoxide Hydrolases; D000626:Aminopeptidases; C043134:leukotriene A4 hydrolase
keywords: E. Coli PepN; metallo-aminopeptidases; selective inhibitors; transition state analogues