Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pneumophila

doi:10.1074/jbc.M109.038364

	Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pneumophila
	Fong, Desiree H.3; Lemke, Christopher T.2,4; Hwang, Jiyoung 1,3; Xiong, Bing4,5 ; Berghuis, Albert M.3,4
刊名	Journal of Biological Chemistry
	2010-03-26
卷号	285 期号:13 页码:9545-9555
ISSN号	00219258
DOI	10.1074/jbc.M109.038364
文献子类	Article
英文摘要	Aminoglycoside phosphotransferases (APHs) constitute a diverse group of enzymes that are often the underlying cause of aminoglycoside resistance in the clinical setting. Several APHs have been extensively characterized, including the elucidation of the three-dimensional structure of two APH(3′) isozymes and an APH(2″) enzyme. Although many APHs are plasmid-encoded and are capable of inactivating numerous 2-deoxystreptmaine aminoglycosides with multiple regiospecificity, APH(9)-Ia, isolated from Legionella pneumophila, is an unusual enzyme among the APH family for its chromosomal origin and its specificity for a single non-2-deoxystreptamine aminoglycoside substrate, spectinomycin.Wedescribe here the crystal structures of APH(9)-Ia in its apo form, its binary complex with the nucleotide, AMP, and its ternary complex bound with ADP and spectinomycin. The structures reveal that APH(9)-Ia adopts the bilobal protein kinase-fold, analogous to the APH(3′) and APH(2″) enzymes. However, APH(9)-Ia differs significantly from the other two types of APH enzymes in its substrate binding area and that it undergoes a conformation change upon ligand binding. Moreover, kinetic assay experiments indicate that APH(9)-Ia has stringent substrate specificity as it is unable to phosphorylate substrates of choline kinase or methylthioribose kinase despite high structural resemblance. The crystal structures of APH(9)-Ia demonstrate and expand our understanding of the diversity of the APH family, which in turn will facilitate the development of new antibiotics and inhibitors.
语种	英语
出版者	American Society for Biochemistry and Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814, United States
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266990]
专题	药物化学研究室
通讯作者	Berghuis, Albert M.
作者单位	1.Genentech, South San Francisco, CA 94080, United States; 2.Boehringer Ingelheim, Laval, QC H7S 2G5, Canada; 3.Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; 4.Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; 5.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
推荐引用方式 GB/T 7714	Fong, Desiree H.,Lemke, Christopher T.,Hwang, Jiyoung,et al. Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pneumophila[J]. Journal of Biological Chemistry,2010,285(13):9545-9555.
APA	Fong, Desiree H.,Lemke, Christopher T.,Hwang, Jiyoung,Xiong, Bing,&Berghuis, Albert M..(2010).Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pneumophila.Journal of Biological Chemistry,285(13),9545-9555.
MLA	Fong, Desiree H.,et al."Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pneumophila".Journal of Biological Chemistry 285.13(2010):9545-9555.