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Title: Encoding of Promiscuity in an Aminoglycoside Acetyltransferase

Abstract

Aminoglycoside antibiotics are a large family of antibiotics that can be divided into two distinct classes on the basis of the substitution pattern of the central deoxystreptamine ring. Although aminoglycosides are chemically, structurally, and topologically diverse, some aminoglycoside-modifying enzymes (AGMEs) are able to inactivate as many as 15 aminoglycosides from the two main classes, the kanamycin- and neomycin-based antibiotics. In this paper, we present the crystal structure of a promiscuous AGME, aminoglycoside-N3-acetyltransferase-IIIb (AAC-IIIb), in the apo form, in binary drug (sisomicin, neomycin, and paromomycin) and coenzyme A (CoASH) complexes, and in the ternary neomycin–CoASH complex. These data provide a structural framework for interpretation of the thermodynamics of enzyme–ligand interactions and the role of solvent in the recognition of ligands. In combination with the recent structure of an AGME that does not have broad substrate specificity, these structures allow for the direct determination of how antibiotic promiscuity is encoded in some AGMEs.

Authors:
 [1];  [2]; ORCiD logo [3]; ORCiD logo [4]
  1. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Neutron Sciences Directorate
  3. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); National Science Foundation (NSF), Alexandria, VA (United States)
  4. St. Jude Children’s Research Hospital, Memphis, TN (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); National Science Foundation (NSF)
OSTI Identifier:
1484803
Grant/Contract Number:  
AC02-06CH11357; MCB-1662080
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 22; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Antimicrobial agents; Peptides and proteins; Carbohydrates; Crystal structure; Noncovalent interactions

Citation Formats

Kumar, Prashasti, Selvaraj, Brinda, Serpersu, Engin H., and Cuneo, Matthew J. Encoding of Promiscuity in an Aminoglycoside Acetyltransferase. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b01393.
Kumar, Prashasti, Selvaraj, Brinda, Serpersu, Engin H., & Cuneo, Matthew J. Encoding of Promiscuity in an Aminoglycoside Acetyltransferase. United States. doi:10.1021/acs.jmedchem.8b01393.
Kumar, Prashasti, Selvaraj, Brinda, Serpersu, Engin H., and Cuneo, Matthew J. Mon . "Encoding of Promiscuity in an Aminoglycoside Acetyltransferase". United States. doi:10.1021/acs.jmedchem.8b01393. https://www.osti.gov/servlets/purl/1484803.
@article{osti_1484803,
title = {Encoding of Promiscuity in an Aminoglycoside Acetyltransferase},
author = {Kumar, Prashasti and Selvaraj, Brinda and Serpersu, Engin H. and Cuneo, Matthew J.},
abstractNote = {Aminoglycoside antibiotics are a large family of antibiotics that can be divided into two distinct classes on the basis of the substitution pattern of the central deoxystreptamine ring. Although aminoglycosides are chemically, structurally, and topologically diverse, some aminoglycoside-modifying enzymes (AGMEs) are able to inactivate as many as 15 aminoglycosides from the two main classes, the kanamycin- and neomycin-based antibiotics. In this paper, we present the crystal structure of a promiscuous AGME, aminoglycoside-N3-acetyltransferase-IIIb (AAC-IIIb), in the apo form, in binary drug (sisomicin, neomycin, and paromomycin) and coenzyme A (CoASH) complexes, and in the ternary neomycin–CoASH complex. These data provide a structural framework for interpretation of the thermodynamics of enzyme–ligand interactions and the role of solvent in the recognition of ligands. In combination with the recent structure of an AGME that does not have broad substrate specificity, these structures allow for the direct determination of how antibiotic promiscuity is encoded in some AGMEs.},
doi = {10.1021/acs.jmedchem.8b01393},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 22,
volume = 61,
place = {United States},
year = {2018},
month = {10}
}

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