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

Journal Article · Tue Nov 17 00:00:00 EST 2015 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.5b01008· OSTI ID:1248621

Rudolf, Jeffrey D. ^[1]; Bigelow, Lance ^[2]; Chang, Changsoo ^[2]; Cuff, Marianne E. ^[2]; Lohman, Jeremy R. ^[1]; Chang, Chin-Yuan ^[1]; Ma, Ming ^[1]; Yang, Dong ^[1]; Clancy, Shonda ^[2]; Babnigg, Gyorgy ^[2]; Joachimiak, Andrzej ^[2]; Phillips, George N. ^[3]; Shen, Ben ^[1]

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1. Scripps Research Inst., Jupiter, FL (United States)
2. Argonne National Lab. (ANL), Argonne, IL (United States)
3. Rice Univ., Houston, TX (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 angstrom, 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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER)
• DOE Contract Number: AC02-06CH11357
• OSTI ID: 1248621
• Journal Information: Biochemistry, Vol. 54, Issue 45; ISSN 0006-2960
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES