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J. Biol. Chem., Vol. 276, Issue 13, 9992-9999, March 30, 2001

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Crystal Structures of the Transposon Tn5-carried Bleomycin Resistance Determinant Uncomplexed and Complexed with Bleomycin^*

Masafumi Maruyama, Takanori Kumagai, Yasuyuki Matoba, Minoru Hayashida, Tomomi Fujii^§, Yasuo Hata^§, and Masanori Sugiyama^¶

From the  Institute of Pharmaceutical Sciences, Faculty of Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551 and the ^§ Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan

The transposon Tn5 carries a gene designated ble that confers resistance to bleomycin (Bm). In this study, we determined the x-ray crystal structures of the ble gene product, designated BLMT, uncomplexed and complexed with Bm at 1.7 and 2.5 Å resolution, respectively. The structure of BLMT is a dimer with two Bm-binding pockets composed of two large concavities and two long grooves. This crystal structure of BLMT complexed with Bm gives a precise mode for binding of the antibiotic to BLMT. The conformational change of BLMT generated by binding to Bm occurs at a -turn composed of the residues from Gln⁹⁷ to Thr¹⁰². Crystallographic analysis of Bm bound to BLMT shows that two thiazolium rings of the bithiazole moiety are in the trans conformation. The axial ligand, which binds a metal ion, seems to be the primary amine in the -aminoalanine moiety. This report, which is the first with regard to the x-ray crystal structure of Bm, shows that the bithiazole moiety of Bm is far from the metal-binding domain. That is, Bm complexed with BLMT takes a more extended form than the drug complexed with DNA.

The atomic coordinates and the structure factors (code 1ecs for BLMT uncomplexed with bleomycin (Bm) and code 1ewj for BLMT complexed with Bm) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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