Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892

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dc.citation.firstpage6842
dc.citation.issueNumber45
dc.citation.journalTitleBiochemistry
dc.citation.lastpage6851
dc.citation.volumeNumber54
dc.contributor.authorRudolf, Jeffrey D.
dc.contributor.authorBigelow, Lance
dc.contributor.authorChang, Changsoo
dc.contributor.authorCuff, Marianne E.
dc.contributor.authorLohman, Jeremy R.
dc.contributor.authorChang, Chin-Yuan
dc.contributor.authorMa, Ming
dc.contributor.authorYang, Dong
dc.contributor.authorClancy, Shonda
dc.contributor.authorBabnigg, Gyorgy
dc.contributor.authorJoachimiak, Andrzej
dc.contributor.authorPhillips, George N.Jr.
dc.contributor.authorShen, Ben
dc.date.accessioned2017-05-12T17:10:13Z
dc.date.available2017-05-12T17:10:13Z
dc.date.issued2015
dc.description.abstractThe 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.identifier.citationRudolf, 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.
dc.identifier.doihttp://dx.doi.org/10.1021/acs.biochem.5b01008
dc.identifier.urihttps://hdl.handle.net/1911/94241
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.
dc.titleCrystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
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