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Title: Structure of the γ-D-glutamyl-L-di­amino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases

Journal Article · · Acta Crystallographica. Section F
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  1. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Joint Center for Structural Genomics, http://www.jcsg.org (United States)
  2. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Genomics Institute of the Novartis Research Foundation, San Diego, CA (United States). Protein Sciences Dept.
  3. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Univ. of California, San Diego, La Jolla, CA (United States). Center for Research in Biological Systems
  4. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Sanford–Burnham Medical Research Institute, La Jolla, CA (United States). Program on Bioinformatics and Systems Biology
  5. Joint Center for Structural Genomics, http://www.jcsg.org (United States); The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Biology
  6. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Univ. of California, San Diego, La Jolla, CA (United States). Center for Research in Biological Systems; Sanford–Burnham Medical Research Inst., La Jolla, CA (United States). Program on Bioinformatics and Systems Biology
  7. Joint Center for Structural Genomics, http://www.jcsg.org (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States). Photon Science
  8. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Univ. of California, San Diego, La Jolla, CA (United States). Center for Research in Biological Systems; Sanford–Burnham Medical Research Institute, La Jolla, CA (United States). Program on Bioinformatics and Systems Biology
  9. Joint Center for Structural Genomics, http://www.jcsg.org (United States); Genomics Institute of the Novartis Research Foundation, San Diego, CA (United States). Protein Sciences Dept.; The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Biology
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Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-­diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-­alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); National Center for Research Resources (NCRR); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-76SF00515; U54 GM074898
OSTI ID:
1625799
Journal Information:
Acta Crystallographica. Section F, Vol. 66, Issue 10; ISSN 1744-3091
Publisher:
International Union of CrystallographyCopyright Statement
Country of Publication:
United States
Language:
English

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Insights into Substrate Specificity of NlpC/P60 Cell Wall Hydrolases Containing Bacterial SH3 Domains journal October 2015
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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
biochemistry & molecular biology
biophysics
crystallography
γ-D-glutamyl-L-diamino acid endopeptidase
cell-wall recycling
NlpC/P60
SH3b
cysteine peptidases
enzyme specificity