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Title: A genome-wide structure-based survey of nucleotide binding proteins in M. tuberculosis

Abstract

Nucleoside tri-phosphates (NTP) form an important class of small molecule ligands that participate in, and are essential to a large number of biological processes. Here, we seek to identify the NTP binding proteome (NTPome) in M. tuberculosis (M.tb), a deadly pathogen. Identifying the NTPome is useful not only for gaining functional insights of the individual proteins but also for identifying useful drug targets. From an earlier study, we had structural models of M.tb at a proteome scale from which a set of 13,858 small molecule binding pockets were identified. We use a set of NTP binding sub-structural motifs derived from a previous study and scan the M.tb pocketome, and find that 1,768 proteins or 43% of the proteome can theoretically bind NTP ligands. Using an experimental proteomics approach involving dye-ligand affinity chromatography, we confirm NTP binding to 47 different proteins, of which 4 are hypothetical proteins. Our analysis also provides the precise list of binding site residues in each case, and the probable ligand binding pose. In conclusion, as the list includes a number of known and potential drug targets, the identification of NTP binding can directly facilitate structure-based drug design of these targets.

Authors:
 [1]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [2];  [1];  [3];  [1]
  1. National Mathematics Initiative, Bangalore (India)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Molecular Biophysics Unit Indian Institute of Science, Bangalore (India)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1411357
Report Number(s):
LA-UR-17-24509
Journal ID: ISSN 2045-2322
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Bhagavat, Raghu, Kim, Heung -Bok, Kim, Chang -Yub, Terwilliger, Thomas Charles, Mehta, Dolly, Srinivasan, Narayanaswamy, and Chandra, Nagasuma. A genome-wide structure-based survey of nucleotide binding proteins in M. tuberculosis. United States: N. p., 2017. Web. doi:10.1038/s41598-017-12471-8.
Bhagavat, Raghu, Kim, Heung -Bok, Kim, Chang -Yub, Terwilliger, Thomas Charles, Mehta, Dolly, Srinivasan, Narayanaswamy, & Chandra, Nagasuma. A genome-wide structure-based survey of nucleotide binding proteins in M. tuberculosis. United States. doi:10.1038/s41598-017-12471-8.
Bhagavat, Raghu, Kim, Heung -Bok, Kim, Chang -Yub, Terwilliger, Thomas Charles, Mehta, Dolly, Srinivasan, Narayanaswamy, and Chandra, Nagasuma. Mon . "A genome-wide structure-based survey of nucleotide binding proteins in M. tuberculosis". United States. doi:10.1038/s41598-017-12471-8. https://www.osti.gov/servlets/purl/1411357.
@article{osti_1411357,
title = {A genome-wide structure-based survey of nucleotide binding proteins in M. tuberculosis},
author = {Bhagavat, Raghu and Kim, Heung -Bok and Kim, Chang -Yub and Terwilliger, Thomas Charles and Mehta, Dolly and Srinivasan, Narayanaswamy and Chandra, Nagasuma},
abstractNote = {Nucleoside tri-phosphates (NTP) form an important class of small molecule ligands that participate in, and are essential to a large number of biological processes. Here, we seek to identify the NTP binding proteome (NTPome) in M. tuberculosis (M.tb), a deadly pathogen. Identifying the NTPome is useful not only for gaining functional insights of the individual proteins but also for identifying useful drug targets. From an earlier study, we had structural models of M.tb at a proteome scale from which a set of 13,858 small molecule binding pockets were identified. We use a set of NTP binding sub-structural motifs derived from a previous study and scan the M.tb pocketome, and find that 1,768 proteins or 43% of the proteome can theoretically bind NTP ligands. Using an experimental proteomics approach involving dye-ligand affinity chromatography, we confirm NTP binding to 47 different proteins, of which 4 are hypothetical proteins. Our analysis also provides the precise list of binding site residues in each case, and the probable ligand binding pose. In conclusion, as the list includes a number of known and potential drug targets, the identification of NTP binding can directly facilitate structure-based drug design of these targets.},
doi = {10.1038/s41598-017-12471-8},
journal = {Scientific Reports},
number = 1,
volume = 7,
place = {United States},
year = {2017},
month = {10}
}

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