| Title | The crystal structure of the D-alanine-D-alanine ligase from Acinetobacter baumannii suggests a flexible conformational change in the central domain before nucleotide binding |
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| Author | Kim-Hung Huynh1, Myoung-ki Hong1, Clarice Lee1,2, Huyen-Thi Tran1, Sang Hee Lee3, Yeh-Jin Ahn4, Sun-Shin Cha5, and Lin-Woo Kang1* |
| Address | 1Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea, 2The Lawrenceville School, Lawrenceville, NJ, USA, 3National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, Yongin 449-728, Republic of Korea, 4Department of Life Science, Sangmyung University, Seoul 110-743, Republic of Korea, 5Marine Biotechnology Research Division, Korea Institute of Ocean Science and Technology, Ansan 426-744, Republic of Korea |
| Bibliography | Journal of Microbiology, 53(11),776-782, 2015, |
| DOI | 10.1007/s12275-015-5475-8 |
| Key Words | D-alanine-D-alanine ligase, drug target, bacterial cell wall synthesis, Acinetobacter baumannii, X-ray crystallography |
| Abstract | Acinetobacter baumannii, which is emerging as a multidrugresistant nosocomial pathogen, causes a number of diseases, including pneumonia, bacteremia, meningitis, and skin infections. With ATP hydrolysis, the D-alanine-D-alanine ligase (DDL) catalyzes the synthesis of D-alanyl-D-alanine, which is an essential component of bacterial peptidoglycan. In this study, we determined the crystal structure of DDL from A. baumannii (AbDDL) at a resolution of 2.2 Å. The asymmetric unit contained six protomers of AbDDL. Five protomers had a closed conformation in the central domain, while one protomer had an open conformation in the central domain. The central domain with an open conformation did not interact with crystallographic symmetry-related protomers and the conformational change of the central domain was not due to crystal packing. The central domain of AbDDL can have an ensemble of the open and closed conformations before the binding of substrate ATP. The conformational change of the central domain is important for the catalytic activity and the detail information will be useful for the development of inhibitors against AbDDL and putative antibacterial agents against A. baumannii. The AbDDL structure was compared with that of other DDLs that were in complex with potent inhibitors and the catalytic activity of AbDDL was confirmed using enzyme kinetics assays. |