Rudolf, Jeffrey D.Bigelow, LanceChang, ChangsooCuff, Marianne E.Lohman, Jeremy R.Chang, Chin-YuanMa, MingYang, DongClancy, ShondaBabnigg, GyorgyJoachimiak, AndrzejPhillips, George N.Jr.Shen, Ben2017-05-122017-05-122015Rudolf, Jeffrey D., Bigelow, Lance, Chang, Changsoo, et al.. "Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892." <i>Biochemistry,</i> 54, no. 45 (2015) American Chemical Society: 6842-6851. http://dx.doi.org/10.1021/acs.biochem.5b01008.https://hdl.handle.net/1911/94241The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM-producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at least two self-resistance elements, an N-acetyltransferase and a binding protein. The N-acetyltransferase provides resistance by disrupting the metal-binding domain of the antibiotic that is required for activity, while the binding protein confers resistance by sequestering the metal-bound antibiotic and preventing drug activation via molecular oxygen. We recently established that the ZBM producer, Streptomyces flavoviridis ATCC21892, lacks the N-acetyltransferase resistance gene and that the ZBM-binding protein, ZbmA, is sufficient to confer resistance in the producing strain. To investigate the resistance mechanism attributed to ZbmA, we determined the crystal structures of apo and Cu(II)-ZBM-bound ZbmA at high resolutions of 1.90 and 1.65 Å, respectively. A comparison and contrast with other structurally characterized members of the BLM-binding protein family revealed key differences in the protein–ligand binding environment that fine-tunes the ability of ZbmA to sequester metal-bound ZBM and supports drug sequestration as the primary resistance mechanism in the producing organisms of the BLM family of antitumor antibiotics.engThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.Journal articlehttp://dx.doi.org/10.1021/acs.biochem.5b01008