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Title: Increasing the structural coverage of tuberculosis drug targets

Abstract

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,more » 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.« less

Authors:
 [1];  [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [3];  [3];  [1];  [4];  [5];  [5];  [5];  [5];  [5];  [1] more »;  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [6];  [1];  [7];  [2];  [8];  [9] « less
+ Show Author Affiliations
  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
Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
OSTI Identifier:
1182307
Grant/Contract Number:  
HHSN272200700057C; HHSN272201200025C
Resource Type:
Accepted Manuscript
Journal Name:
Tuberculosis
Additional Journal Information:
Journal Volume: 95; Journal Issue: 2; Journal ID: ISSN 1472-9792
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Drug discovery; homolog-rescue; structural genomics; enzyme active site

Citation Formats

Baugh, Loren, Phan, Isabelle, Begley, Darren W., Clifton, Matthew C., Armour, Brianna, Dranow, David M., Taylor, Brandy M., Muruthi, Marvin M., Abendroth, Jan, Fairman, James W., Fox, David, Dieterich, Shellie H., Staker, Bart L., Gardberg, Anna S., Choi, Ryan, Hewitt, Stephen N., Napuli, Alberto J., Myers, Janette, Barrett, Lynn K., Zhang, Yang, Ferrell, Micah, Mundt, Elizabeth, Thompkins, Katie, Tran, Ngoc, Lyons-Abbott, Sally, Abramov, Ariel, Sekar, Aarthi, Serbzhinskiy, Dmitri, Lorimer, Don, Buchko, Garry W., Stacy, Robin, Stewart, Lance J., Edwards, Thomas E., Van Voorhis, Wesley C., and Myler, Peter J. Increasing the structural coverage of tuberculosis drug targets. United States: N. p., 2014. Web. doi:10.1016/j.tube.2014.12.003.
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Baugh, Loren, Phan, Isabelle, Begley, Darren W., Clifton, Matthew C., Armour, Brianna, Dranow, David M., Taylor, Brandy M., Muruthi, Marvin M., Abendroth, Jan, Fairman, James W., Fox, David, Dieterich, Shellie H., Staker, Bart L., Gardberg, Anna S., Choi, Ryan, Hewitt, Stephen N., Napuli, Alberto J., Myers, Janette, Barrett, Lynn K., Zhang, Yang, Ferrell, Micah, Mundt, Elizabeth, Thompkins, Katie, Tran, Ngoc, Lyons-Abbott, Sally, Abramov, Ariel, Sekar, Aarthi, Serbzhinskiy, Dmitri, Lorimer, Don, Buchko, Garry W., Stacy, Robin, Stewart, Lance J., Edwards, Thomas E., Van Voorhis, Wesley C., & Myler, Peter J. Increasing the structural coverage of tuberculosis drug targets. United States. https://doi.org/10.1016/j.tube.2014.12.003
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Baugh, Loren, Phan, Isabelle, Begley, Darren W., Clifton, Matthew C., Armour, Brianna, Dranow, David M., Taylor, Brandy M., Muruthi, Marvin M., Abendroth, Jan, Fairman, James W., Fox, David, Dieterich, Shellie H., Staker, Bart L., Gardberg, Anna S., Choi, Ryan, Hewitt, Stephen N., Napuli, Alberto J., Myers, Janette, Barrett, Lynn K., Zhang, Yang, Ferrell, Micah, Mundt, Elizabeth, Thompkins, Katie, Tran, Ngoc, Lyons-Abbott, Sally, Abramov, Ariel, Sekar, Aarthi, Serbzhinskiy, Dmitri, Lorimer, Don, Buchko, Garry W., Stacy, Robin, Stewart, Lance J., Edwards, Thomas E., Van Voorhis, Wesley C., and Myler, Peter J. Fri . "Increasing the structural coverage of tuberculosis drug targets". United States. https://doi.org/10.1016/j.tube.2014.12.003. https://www.osti.gov/servlets/purl/1182307.
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@article{osti_1182307,
title = {Increasing the structural coverage of tuberculosis drug targets},
author = {Baugh, Loren and Phan, Isabelle and Begley, Darren W. and Clifton, Matthew C. and Armour, Brianna and Dranow, David M. and Taylor, Brandy M. and Muruthi, Marvin M. and Abendroth, Jan and Fairman, James W. and Fox, David and Dieterich, Shellie H. and Staker, Bart L. and Gardberg, Anna S. and Choi, Ryan and Hewitt, Stephen N. and Napuli, Alberto J. and Myers, Janette and Barrett, Lynn K. and Zhang, Yang and Ferrell, Micah and Mundt, Elizabeth and Thompkins, Katie and Tran, Ngoc and Lyons-Abbott, Sally and Abramov, Ariel and Sekar, Aarthi and Serbzhinskiy, Dmitri and Lorimer, Don and Buchko, Garry W. and Stacy, Robin and Stewart, Lance J. and Edwards, Thomas E. and Van Voorhis, Wesley C. and Myler, Peter J.},
abstractNote = {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.},
doi = {10.1016/j.tube.2014.12.003},
journal = {Tuberculosis},
number = 2,
volume = 95,
place = {United States},
year = {Fri Dec 19 00:00:00 EST 2014},
month = {Fri Dec 19 00:00:00 EST 2014}
}
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https://doi.org/10.1016/j.tube.2014.12.003
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Works referenced in this record:

Drugs for bad bugs: confronting the challenges of antibacterial discovery
journal, December 2006

  • Payne, David J.; Gwynn, Michael N.; Holmes, David J.
  • Nature Reviews Drug Discovery, Vol. 6, Issue 1
  • DOI: 10.1038/nrd2201

PRO_SELECT:  Combining Structure-Based Drug Design and Array-Based Chemistry for Rapid Lead Discovery. 2. The Development of a Series of Highly Potent and Selective Factor Xa Inhibitors
journal, February 2002

  • Liebeschuetz, John W.; Jones, Stuart D.; Morgan, Phillip J.
  • Journal of Medicinal Chemistry, Vol. 45, Issue 6
  • DOI: 10.1021/jm010944e

The Seattle Structural Genomics Center for Infectious Disease (SSGCID)
journal, October 2009

A synergistic approach to protein crystallization: Combination of a fixed-arm carrier with surface entropy reduction
journal, January 2010

  • Moon, Andrea F.; Mueller, Geoffrey A.; Zhong, Xuejun
  • Protein Science
  • DOI: 10.1002/pro.368

It's all in the crystals…
journal, March 2011

  • Derewenda, Zygmunt S.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444911007797

Combined protein construct and synthetic gene engineering for heterologous protein expression and crystallization using Gene Composer
journal, January 2009

Gene Composer: database software for protein construct design, codon engineering, and gene synthesis
journal, January 2009

Genome Pool Strategy for Structural Coverage of Protein Families
journal, November 2008

The quest for orthologs: finding the corresponding gene across genomes
journal, November 2008

  • Kuzniar, Arnold; van Ham, Roeland C. H. J.; Pongor, Sándor
  • Trends in Genetics, Vol. 24, Issue 11
  • DOI: 10.1016/j.tig.2008.08.009

The TB Structural Genomics Consortium: A decade of progress
journal, March 2011

Structural genomics approach to drug discovery for Mycobacterium tuberculosis
journal, June 2009

Structural Genomics and Drug Discovery for Infectious Diseases
journal, October 2009

Strategies for structural proteomics of prokaryotes: Quantifying the advantages of studying orthologous proteins and of using both NMR and X-ray crystallography approaches
journal, January 2003

  • Savchenko, Alexei; Yee, Adelinda; Khachatryan, Anna
  • Proteins: Structure, Function, and Bioinformatics, Vol. 50, Issue 3
  • DOI: 10.1002/prot.10282

Combining Functional and Structural Genomics to Sample the Essential Burkholderia Structome
journal, January 2013

Design of thymidylate synthase inhibitors using protein crystal structures: the synthesis and biological evaluation of a novel class of 5-substituted quinazolinones
journal, March 1993

  • Webber, Stephen E.; Bleckman, Ted M.; Attard, John
  • Journal of Medicinal Chemistry, Vol. 36, Issue 6
  • DOI: 10.1021/jm00058a010

Design of enzyme inhibitors using iterative protein crystallographic analysis
journal, July 1991

  • Appelt, Krzysztof; Bacquet, Russell J.; Bartlett, Charlotte A.
  • Journal of Medicinal Chemistry, Vol. 34, Issue 7
  • DOI: 10.1021/jm00111a001

Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids
journal, December 1977

  • Cushman, D. W.; Cheung, H. S.; Sabo, E. F.
  • Biochemistry, Vol. 16, Issue 25
  • DOI: 10.1021/bi00644a014

Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors
journal, June 2012

  • Ojo, Kayode K.; Pfander, Claudia; Mueller, Natascha R.
  • Journal of Clinical Investigation, Vol. 122, Issue 6
  • DOI: 10.1172/JCI61822

A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis
journal, January 2005

Twilight zone of protein sequence alignments
journal, February 1999

The Protein Data Bank
journal, January 2000

The relation between the divergence of sequence and structure in proteins.
journal, April 1986

Large-scale protein structure modeling of the Saccharomyces cerevisiae genome
journal, November 1998

  • Sanchez, R.; Sali, A.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 23
  • DOI: 10.1073/pnas.95.23.13597

Assessing Performance of Orthology Detection Strategies Applied to Eukaryotic Genomes
journal, April 2007

Interplay of physics and evolution in the likely origin of protein biochemical function
journal, May 2013

  • Skolnick, Jeffrey; Gao, Mu
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 23
  • DOI: 10.1073/pnas.1300011110

How Well is Enzyme Function Conserved as a Function of Pairwise Sequence Identity?
journal, October 2003

Role of Induced Fit in Enzyme Specificity: A Molecular Forward/Reverse Switch
journal, June 2008

Purine Salvage Pathway in Mycobacterium tuberculosis
journal, March 2011

Pyrimidine Salvage Pathway in Mycobacterium tuberculosis
journal, March 2011

  • D. Villela, A.; A. Sanchez-Quitian, Z.; G. Ducati, R.
  • Current Medicinal Chemistry, Vol. 18, Issue 9
  • DOI: 10.2174/092986711795029555

Genes required for mycobacterial growth defined by high density mutagenesis: Genes required for mycobacterial growth
journal, March 2003

High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and Cholesterol Catabolism
journal, September 2011

Sugar specificity of bacterial CMP kinases as revealed by crystal structures and mutagenesis of Escherichia coli enzyme
journal, February 2002

  • Bertrand, Thomas; Briozzo, Pierre; Assairi, Liliane
  • Journal of Molecular Biology, Vol. 315, Issue 5
  • DOI: 10.1006/jmbi.2001.5286

High-throughput protein production and purification at the Seattle Structural Genomics Center for Infectious Disease
journal, August 2011

  • Bryan, Cassie M.; Bhandari, Janhavi; Napuli, Alberto J.
  • Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 67, Issue 9
  • DOI: 10.1107/S1744309111018367

Structural genomics of infectious disease drug targets: the SSGCID
journal, August 2011

  • Stacy, Robin; Begley, Darren W.; Phan, Isabelle
  • Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 67, Issue 9
  • DOI: 10.1107/S1744309111029204

Immobilized metal-affinity chromatography protein-recovery screening is predictive of crystallographic structure success
journal, August 2011

  • Choi, Ryan; Kelley, Angela; Leibly, David
  • Acta Crystallographica Section F Structural Biology and Crystallization Communications, Vol. 67, Issue 9
  • DOI: 10.1107/S1744309111017374

ICM?A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation
journal, May 1994

  • Abagyan, Ruben; Totrov, Maxim; Kuznetsov, Dmitry
  • Journal of Computational Chemistry, Vol. 15, Issue 5
  • DOI: 10.1002/jcc.540150503

Tools for integrated sequence-structure analysis with UCSF Chimera
journal, July 2006

  • Meng, Elaine C.; Pettersen, Eric F.; Couch, Gregory S.
  • BMC Bioinformatics, Vol. 7, Issue 1
  • DOI: 10.1186/1471-2105-7-339
    Sort by:
    [ × clear filter / sort ]

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    • DOI: 10.3390/ijms19092518

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    journal, November 2019

    • Buchko, Garry W.; Abendroth, Jan; Robinson, John I.
    • Protein Science, Vol. 29, Issue 3
    • DOI: 10.1002/pro.3758

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    journal, August 2018

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    journal, August 2018

    • Abendroth, Jan; Sankaran, Banumathi; Myler, Peter J.
    • Acta Crystallographica Section F Structural Biology Communications, Vol. 74, Issue 9
    • DOI: 10.1107/s2053230x18010063

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    journal, April 2019

    Carboxylic Ester Hydrolases in Bacteria: Active Site, Structure, Function and Application
    journal, November 2019

    • Oh, Changsuk; Kim, T. Doohun; Kim, Kyeong Kyu
    • Crystals, Vol. 9, Issue 11
    • DOI: 10.3390/cryst9110597

    Structures of the calcium-activated, non-selective cation channel TRPM4
    journal, December 2017

    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

    • Ma, Zhongxin; Abendroth, Jan; Buchko, Garry W.
    • Biochemical Journal, Vol. 477, Issue 2
    • DOI: 10.1042/bcj20190827

    Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase
    journal, March 2019

    • Ajalla Aleixo, Mariana A.; Rangel, Victor L.; Rustiguel, Joane K.
    • The FEBS Journal, Vol. 286, Issue 10
    • DOI: 10.1111/febs.14782

    Structural characterization and functional analysis of cystathionine β‐synthase: an enzyme involved in the reverse transsulfuration pathway of Bacillus anthracis
    journal, October 2017

    • Devi, Suneeta; Abdul Rehman, Syed A.; Tarique, Khaja F.
    • The FEBS Journal, Vol. 284, Issue 22
    • DOI: 10.1111/febs.14273

    Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE
    journal, March 2018

    • Rigden, Daniel J.; Thomas, Jens M. H.; Simkovic, Felix
    • Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 3
    • DOI: 10.1107/s2059798318002310

    Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification
    posted_content, May 2019

    • Thomas, Sherine E.; Whitehouse, Andrew J.; Brown, Karen
    • bioRxiv
    • DOI: 10.1101/564013

    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

    • Seo, Hogyun; Kim, Sangwoo; Sagong, Hye-Young
    • Scientific Reports, Vol. 6, Issue 1
    • DOI: 10.1038/srep31390
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