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dc.contributor.authorRudolf, Jeffrey D.
Bigelow, Lance
Chang, Changsoo
Cuff, Marianne E.
Lohman, Jeremy R.
Chang, Chin-Yuan
Ma, Ming
Yang, Dong
Clancy, Shonda
Babnigg, Gyorgy
Joachimiak, Andrzej
Phillips, George N. Jr.
Shen, Ben
dc.date.accessioned 2017-05-12T17:10:13Z
dc.date.available 2017-05-12T17:10:13Z
dc.date.issued 2015
dc.identifier.citation Rudolf, 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." Biochemistry, 54, no. 45 (2015) American Chemical Society: 6842-6851. http://dx.doi.org/10.1021/acs.biochem.5b01008.
dc.identifier.urihttps://hdl.handle.net/1911/94241
dc.description.abstract The 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.
dc.language.iso eng
dc.publisher American Chemical Society
dc.rights This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.
dc.title Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892
dc.type Journal article
dc.citation.journalTitle Biochemistry
dc.citation.volumeNumber 54
dc.citation.issueNumber 45
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1021/acs.biochem.5b01008
dc.identifier.pmcid PMC4809751
dc.identifier.pmid 26512730
dc.type.publication post-print
dc.citation.firstpage 6842
dc.citation.lastpage 6851


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