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PEDS Advance Access published online on May 20, 2009
Protein Engineering Design and Selection, doi:10.1093/protein/gzp014
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Structural insight into the binding mode between the targeting domain of ALE-1 (92AA) and pentaglycine of peptidoglycan

Hideki Hirakawa1, Hidenori Akita2, Tamaki Fujiwara3, Motoyuki Sugai3 and Satoru Kuhara2,4,5

1Faculty of Agriculture 2Graduate School of Systems Life Sciences 3Graduate School of Genetic Resource Technology, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan 4Department of Bacteriology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi, Minami-ku, Hiroshima, Japan

5 To whom correspondence should be addressed. E-mail: kuhara{at}grt.kyushu-u.ac.jp

ALE-1 is a glycylglycine endopeptidase that selectively targets and lyses Staphylococcus aureus, and is expected to be a next generation antibacterial agent because of its substrate specificity to pathogenic bacteria. It has a central catalytic domain and a targeting domain called 92AA. 92AA has been shown to recognize pentaglycine, but the molecular mechanism by which it recognizes and interacts with pentaglycine has not been elucidated. To predict the binding modes of pentaglycine is important for estimating the catalytic reaction mechanism of ALE-1. In the present study, we characterized the binding cleft of 92AA by a computational method and modeled the complexes formed between 92AA and the pentaglycine of peptidoglycan by a binding simulation. In addition, we performed precise simulations of the molecular dynamics by which the complexes identify the amino acid residues interacting with the pentaglycine. We also experimentally constructed mutants in which the amino acid residues present in the binding cleft were changed by site-directed mutagenesis and assessed their ability to bind to peptidoglycan by ELISA. Based on the results of these analyses, we proposed a mode of binding between 92AA and the pentaglycine of peptidoglycan, and modeled the energetically stable complexes between 92AA and the pentaglycine.

Keywords: binding simulation/interpeptide bridge of peptidoglycan/molecular dynamics (MD) simulation/systematic conformational search/targeting domain of ALE-1

Received October 3, 2008; revised April 7, 2009; accepted April 7, 2009.


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