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Title: A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity

Abstract

The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5'-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD +, which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD + and XMP/NAD +. In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD+ adenosine moiety. More importantly, this new NAD +-binding site involves the same pocket that is utilized by the inhibitors. Thus,more » the bacterial IMPDH-specific NAD +-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. As a result, these findings offer a potential strategy for further ligand optimization.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [3];  [3];  [3];  [3];  [3];  [2]
  1. Univ. of Chicago, Chicago, IL (United States)
  2. Univ. of Chicago, Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Brandeis Univ., Waltham, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1225229
Grant/Contract Number:  
AC02–06CH11357; HHSN272200700058C; HHSN272201200026C
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 9; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; antibiotic resistance; enzyme inhibitor; ligand-binding protein; microbial pathogenesis; nicotinamide adenine dinucleotide (NAD); cryptosporidium parvum-selective inhibitors; antibacterial; cofactor-binding site; inosine 5'-monophosphate dehydrogenase

Citation Formats

Makowska-Grzyska, Magdalena, Kim, Youngchang, Maltseva, Natalia, Osipiuk, Jerzy, Gu, Minyi, Zhang, Minjia, Mandapati, Kavitha, Gollapalli, Deviprasad R., Gorla, Suresh Kumar, Hedstrom, Lizbeth, and Joachimiak, Andrzej. A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity. United States: N. p., 2015. Web. doi:10.1074/jbc.M114.619767.
Makowska-Grzyska, Magdalena, Kim, Youngchang, Maltseva, Natalia, Osipiuk, Jerzy, Gu, Minyi, Zhang, Minjia, Mandapati, Kavitha, Gollapalli, Deviprasad R., Gorla, Suresh Kumar, Hedstrom, Lizbeth, & Joachimiak, Andrzej. A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity. United States. doi:10.1074/jbc.M114.619767.
Makowska-Grzyska, Magdalena, Kim, Youngchang, Maltseva, Natalia, Osipiuk, Jerzy, Gu, Minyi, Zhang, Minjia, Mandapati, Kavitha, Gollapalli, Deviprasad R., Gorla, Suresh Kumar, Hedstrom, Lizbeth, and Joachimiak, Andrzej. Fri . "A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity". United States. doi:10.1074/jbc.M114.619767. https://www.osti.gov/servlets/purl/1225229.
@article{osti_1225229,
title = {A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity},
author = {Makowska-Grzyska, Magdalena and Kim, Youngchang and Maltseva, Natalia and Osipiuk, Jerzy and Gu, Minyi and Zhang, Minjia and Mandapati, Kavitha and Gollapalli, Deviprasad R. and Gorla, Suresh Kumar and Hedstrom, Lizbeth and Joachimiak, Andrzej},
abstractNote = {The steadily rising frequency of emerging diseases and antibiotic resistance creates an urgent need for new drugs and targets. Inosine 5'-monophosphate dehydrogenase (IMP dehydrogenase or IMPDH) is a promising target for the development of new antimicrobial agents. IMPDH catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD+, which is the pivotal step in the biosynthesis of guanine nucleotides. Potent inhibitors of bacterial IMPDHs have been identified that bind in a structurally distinct pocket that is absent in eukaryotic IMPDHs. The physiological role of this pocket was not understood. Here, we report the structures of complexes with different classes of inhibitors of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDHs. These structures in combination with inhibition studies provide important insights into the interactions that modulate selectivity and potency. We also present two structures of the Vibrio cholerae IMPDH in complex with IMP/NAD+ and XMP/NAD+. In both structures, the cofactor assumes a dramatically different conformation than reported previously for eukaryotic IMPDHs and other dehydrogenases, with the major change observed for the position of the NAD+ adenosine moiety. More importantly, this new NAD+-binding site involves the same pocket that is utilized by the inhibitors. Thus, the bacterial IMPDH-specific NAD+-binding mode helps to rationalize the conformation adopted by several classes of prokaryotic IMPDH inhibitors. As a result, these findings offer a potential strategy for further ligand optimization.},
doi = {10.1074/jbc.M114.619767},
journal = {Journal of Biological Chemistry},
number = 9,
volume = 290,
place = {United States},
year = {2015},
month = {1}
}

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