Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis
Résumé
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 microM) 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. (c) 2017 Wiley Periodicals, Inc.
Mots clés
Amino Acid Motifs
Anisoles/*chemistry
Catalytic Domain
Cloning
Molecular
Crystallography
X-Ray
Cycloheptanes/*chemistry
Epoxide Hydrolases/chemistry/genetics/metabolism
Escherichia coli/*chemistry/enzymology/genetics
Gene Expression
Humans
Kinetics
Models
Protease Inhibitors/*chemistry
Protein Binding
Protein Conformation
alpha-Helical
beta-Strand
Protein Interaction Domains and Motifs
Recombinant Proteins/chemistry/genetics/metabolism
Sequence Alignment
Structural Homology
Protein
Substrate Specificity
Thermodynamics
E. Coli PepN
metallo-aminopeptidases
selective inhibitors
transition state analogues