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Structural basis for substrate recognition and reaction mechanism of a bacterial aminopeptidase

2009년 8월 21일 21시 17분 23초
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생명화학 - Biochemistry of Protein Structures and Functions
저자 및
성균관대학교 생명과학과, Korea
The substrate specificities of aminopeptidases must be tightly regulated to prevent unwanted peptide cleavage otherwise damaging essential cellular functions. Bacterial aminopeptidase PepS shows substrate specificity towards small peptides possessing arginine or aromatic residues at the N-terminus, but mechanisms underlying this specificity remain elusive. Here we report the crystal structures of PepS from Streptococcus pneumoniae in two conformations and its complexes with a substrate or inhibitors. PepS exists as an elongated dimer where each monomer consists of N- and C-terminal domains. The relative orientation of the two domains permits PepS to adopt at least two distinct conformations: closed and open. The closed, active conformation of PepS limits the substrate entry, while the open, inactive conformation accommodates the substrates into its binding pocket with the catalytic residues positioned away from the active configuration. The closed dimer features face-to-face, eclipsed arrangement and the open dimer have two monomers in staggered position. Substrate recognition is achieved by two kinds of filters: S1 substrate binding pocket determining the identity of the cleaving residue (“specificity filter”) and internal cavity and elongated dimeric arrangement limiting the length of the substrate (“length filter”). We propose that PepS alternates between open and closed conformations by domain movements during each catalytic cycle: opening for swallowing in the substrate, closing for the hydrolysis of the bound substrate, and re-opening for the release of the products.