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Biochemistry. 2015 Nov 17;54(45):6842-51. doi: 10.1021/acs.biochem.5b01008. Epub 2015 Nov 5.

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

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Department of Chemistry, The Scripps Research Institute , Jupiter, Florida 33458, United States.
Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory , Argonne, Illinois 60439, United States.
BioSciences at Rice and Department of Chemistry, Rice University , Houston, Texas 77251, United States.
Department of Molecular Therapeutics, The Scripps Research Institute , Jupiter, Florida 33458, United States.
Natural Products Library Initiative, The Scripps Research Institute , Jupiter, Florida 33458, United States.


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.

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