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Title: Increasing the structural coverage of tuberculosis drug targets

Journal Article · · Tuberculosis
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  1. Seattle Structural Genomics Center for Infectious Disease (United States); Seattle Biomedical Research Inst., Seattle, WA (United States)
  2. Seattle Structural Genomics Center for Infectious Disease (United States); Beryllium, Bainbridge Island, WA (United States)
  3. Beryllium, Bainbridge Island, WA (United States)
  4. Seattle Structural Genomics Center for Infectious Disease (United States); Beryllium, Bainbridge Island, WA (United States); EMD Serono Research & Development Inst., Inc., Billerica, MA (United States)
  5. Seattle Structural Genomics Center for Infectious Disease (United States); Univ. of Washington, Seattle, WA (United States). Dept. of Medicine
  6. Seattle Structural Genomics Center for Infectious Disease (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
  7. Seattle Structural Genomics Center for Infectious Disease (United States); Beryllium, Bainbridge Island, WA (United States); Univ. of Washington, Seattle, WA (United States). Inst. for Protein Design
  8. Seattle Structural Genomics Center for Infectious Disease (United States); Univ. of Washington, Seattle, WA (United States). Dept. of Medicine; Univ. of Washington, Seattle, WA (United States). Dept. of Global Health; Univ. of Washington, Seattle, WA (United States). Dept. of Microbiology
  9. Seattle Structural Genomics Center for Infectious Disease (United States); Seattle Biomedical Research Inst., Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States). Dept. of Global Health; Univ. of Washington, Seattle, WA (United States). Dept. of Biomedical Informatics and Medical Education
+ Show Author Affiliations

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.

Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
Grant/Contract Number:
HHSN272200700057C; HHSN272201200025C
OSTI ID:
1182307
Journal Information:
Tuberculosis, Vol. 95, Issue 2; ISSN 1472-9792
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 89 works
Citation information provided by
Web of Science

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Biochemical Characterization and Structural Modeling of Fused Glucose-6-Phosphate Dehydrogenase-Phosphogluconolactonase from Giardia lamblia journal August 2018
Structural diversity in the Mycobacteria DUF3349 superfamily journal November 2019
Investigation of the anti-TB potential of selected propolis constituents using a molecular docking approach journal August 2018
Insights into multifaceted activities of CysK for therapeutic interventions journal January 2019
Ab initio structure solution of a proteolytic fragment using ARCIMBOLDO journal August 2018
Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS) journal April 2019
Carboxylic Ester Hydrolases in Bacteria: Active Site, Structure, Function and Application journal November 2019
Structures of the calcium-activated, non-selective cation channel TRPM4 journal December 2017
Spontaneous mutations conferring antibiotic resistance to antitubercular drugs at a range of concentrations in Mycobacterium smegmatis journal December 2018
Structural and functional insight into serine hydroxymethyltransferase from Helicobacter pylori journal December 2018
Crystal structure of a hemerythrin-like protein from Mycobacterium kansasii and homology model of the orthologous Rv2633c protein of M. tuberculosis journal January 2020
Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase journal March 2019
Determinants of Cofactor Specificity for the Glucose-6-Phosphate Dehydrogenase from Escherichia coli: Simulation, Kinetics and Evolutionary Studies journal March 2016
Structural characterization and functional analysis of cystathionine β‐synthase: an enzyme involved in the reverse transsulfuration pathway of Bacillus anthracis journal October 2017
Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE journal March 2018
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification posted_content May 2019
Integrated Target‐Based and Phenotypic Screening Approaches for the Identification of Anti‐Tubercular Agents That Bind to the Mycobacterial Adenylating Enzyme MbtA journal September 2019
Investigation of pyrophosphate versus ATP substrate selection in the Entamoeba histolytica acetate kinase journal July 2017
Structural basis for cytokinin production by LOG from Corynebacterium glutamicum journal August 2016

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Drug discovery
homolog-rescue
structural genomics
enzyme active site