Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Structural and functional analyses of the echinomycin resistance conferring protein Ecm16 from Streptomyces lasalocidi

Journal Article · · Scientific Reports
 [1];  [2];  [1];  [3];  [4];  [2];  [5]
  1. Univ. of Texas at El Paso, TX (United States)
  2. Univ. of Illinois at Urbana-Champaign, IL (United States)
  3. Northwest University (China)
  4. SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
  5. Univ. of Texas at El Paso, TX (United States); Univ. of Illinois at Urbana-Champaign, IL (United States)
+ Show Author Affiliations

Echinomycin is a natural product DNA bisintercalator antibiotic. The echinomycin biosynthetic gene cluster in Streptomyces lasalocidi includes a gene encoding the self-resistance protein Ecm16. Here, we present the 2.0 Å resolution crystal structure of Ecm16 bound to adenosine diphosphate. The structure of Ecm16 closely resembles that of UvrA, the DNA damage sensor component of the prokaryotic nucleotide excision repair system, but Ecm16 lacks the UvrB-binding domain and its associated zinc-binding module found in UvrA. Mutagenesis study revealed that the insertion domain of Ecm16 is required for DNA binding. Furthermore, the specific amino acid sequence of the insertion domain allows Ecm16 to distinguish echinomycin-bound DNA from normal DNA and link substrate binding to ATP hydrolysis activity. Expression of ecm16 in the heterologous host Brevibacillus choshinensis conferred resistance against echinomycin and other quinomycin antibiotics, including thiocoraline, quinaldopeptin, and sandramycin. Our study provides new insight into how the producers of DNA bisintercalator antibiotics fend off the toxic compounds that they produce.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States); Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-76SF00515; AC02-06CH11357; P41GM103393
OSTI ID:
2001433
Journal Information:
Scientific Reports, Vol. 13, Issue 1; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (27)

Complete sequence of biosynthetic gene cluster responsible for producing triostin A and evaluation of quinomycin-type antibiotics from Streptomyces triostinicus journal November 2008
In Vitro Characterization of Echinomycin Biosynthesis: Formation and Hydroxylation of L-Tryptophanyl-S-Enzyme and Oxidation of (2S,3S) β-Hydroxytryptophan journal February 2013
The UvrA‐like protein Ecm16 requires ATPase activity to render resistance against echinomycin journal May 2022
Role of the insertion domain and the zinc-finger motif of Escherichia coli UvrA in damage recognition and ATP hydrolysis journal May 2011
Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli journal June 2006
In vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus journal November 2007
Structure of UvrA nucleotide excision repair protein in complex with modified DNA journal January 2011
Structural Biology of Rad50 ATPase journal June 2000
New Insights into the Mechanism of the DNA/Doxorubicin Interaction journal January 2014
In vitro antibacterial activity of echinomycin and a novel analogue, YK2000, against vancomycin-resistant enterococci journal December 2004
Coot model-building tools for molecular graphics journal November 2004
A New Scaffold of an Old Protein Fold Ensures Binding to the Bisintercalator Thiocoraline journal March 2010
Prokaryotic Nucleotide Excision Repair:  The UvrABC System journal February 2006
High-Level Production of Recombinant Chicken Interferon-γ by Brevibacillus choshinensis journal October 2001
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Conversion of a Disulfide Bond into a Thioacetal Group during Echinomycin Biosynthesis journal December 2013
Macromolecular TLS Refinement in REFMAC at Moderate Resolutions book January 2003
Data processing and analysis with the autoPROC toolbox journal March 2011
Base Specificity in the Interaction of Polynucleotides with Antibiotic Drugs journal September 1965
Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies journal January 2007
Structural and Mutational Analyses of Deinococcus radiodurans UvrA2 Provide Insight into DNA Binding and Damage Recognition by UvrAs journal April 2009
The Streptomyces peucetius drrC gene encodes a UvrA-like protein involved in daunorubicin resistance and production journal June 1996
Deciphering the Biosynthesis Pathway of the Antitumor Thiocoraline from a Marine Actinomycete and Its Expression in Two Streptomyces Species journal January 2006
Crystal Structure of Bacillus stearothermophilus UvrA Provides Insight into ATP-Modulated Dimerization, UvrB Interaction, and DNA Binding journal January 2008
Structure and function of ABC transporters: the ATP switch provides flexible control journal August 2006
Phaser crystallographic software journal July 2007
Stoffwechselprodukte von Actinomyceten. 7. Mitteilung. Echinomycin journal January 1957

Similar Records

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
biochemistry
microbiology
structural biology