PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Protein Folding and Misfolding: It's the Journey, Not the Destination
March 2015
CCR5 and HIV Infection
January 2015
HIV/AIDS: Pre-fusion Env Exposed
January 2015
HIV/AIDS: Slide to Enter
January 2015
Updating ModBase
January 2015
Power in Numbers
August 2014
Quorum Sensing: A Groovy New Component
August 2014
Bacterial CDI Toxins
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Virology: A Bat Influenza Hemagglutinin
March 2014
Virology: Making Sensitive Magic
March 2014
Virology: Visualizing Cyanophage Assembly
March 2014
Virology: Zeroing in on HBV Egress
March 2014
March 2014
Cas4 Nuclease and Bacterial Immunity
February 2014
Microbial Pathogenesis: A GNAT from Pseudomonas
February 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Microbiome: The Dynamics of Infection
September 2013
Membrane Proteome: A Funnel-like Viroporin
August 2013
Infectious Diseases: A Pathogen Ubiquitin Ligase
May 2013
Infectious Diseases: A Shared Syringe
May 2013
Infectious Diseases: Determining the Essential Structome
May 2013
Infectious Diseases: Targeting Meningitis
May 2013
NDM-1 and Antibiotics
May 2013
Bacterial Hemophores
January 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Microbial Pathogenesis: NEAT Iron
January 2013
Membrane Proteome: Sphingolipid Synthesis Selectivity
December 2012
A signal sensing switch
September 2012
Gauging needle structure
July 2012
Anthrax Stealth Siderophores
June 2012
A Pseudomonas L-serine dehydrogenase
May 2012
Pilus Assembly Protein TadZ
April 2012
Making Lipopolysaccharide
January 2012
Superbugs and Antibiotic Resistance
December 2011
A change to resistance
November 2011
An effective and cooperative dimer
November 2011
The Perils of Protein Secretion
November 2011
Bacterial Armor
October 2011
Breaking down the defenses
September 2011
Moving some metal
August 2011
Capsid assembly in motion
April 2011
Know thy enemy … structurally
October 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Hemolysin BL
January 2010
Unusual cell division
October 2009
Anthrax evasion tactics
September 2009
Toxin-antitoxin VapBC-5
September 2009
Antibiotic target
August 2009
July 2009
Tackling influenza
June 2009
You look familiar: the Type VI secretion system
June 2009
Unique SARS
April 2009
Anthrax stealth molecule
March 2009
A new class of bacterial E3 ubiquitination enzymes
January 2009
Antiviral evasion
October 2008
SARS connections
September 2008
SARS Coronavirus Nonstructural Protein 1
June 2008

Research Themes Infectious diseases

Infectious Diseases: Determining the Essential Structome

SBKB [doi:10.1038/sbkb.2012.141]
Technical Highlight - May 2013
Short description: Twenty-five potential drug targets emerge from the Burkholderia structome through an integrated pipeline.

Binding pocket of isochorismatase, an enzyme identified as essential in B. thailandensis by transposon mutagenesis. The pocket structure provides a template for drug design. Figure courtesy of Wesley Van Voorhis.

The bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic to parts of Australia and Southeast Asia. Burkholderia species also cause glanders in animals and pulmonary infections in patients with partially compromised immune systems. The development of new antibiotics is urgently needed, as drug-resistant strains continue to emerge and spread. While structure-based drug design is promising, challenges remain in the search for new antimicrobial agents, such as avoiding the large, non-essential proteome and the difficulties of structure determination.

Overcoming these limitations, Van Voorhis and colleagues (SSCGID) have taken an integrated functional and structural genomics approach to finding potential targets for antibiotics in Burkholderia. First, 406 putative essential genes in the low-virulence B. thailandensis species were identified by saturation-level transposon mutagenesis followed by sequencing. Next, a battery of biological and biochemical criteria narrowed the list down to 315 genes for expression and structure determination.

Typically, the success rate of structure determination from gene candidates is lower than 10%, due to insoluble expression and crystallization difficulties. The authors met this challenge by implementing an “ortholog rescue” in which 387 homologous genes from seven other Burkholderia species were added to the structure-determination pipeline. 450 were expressed in soluble form and 170 crystalized; 68 crystals diffracted with sufficient resolution to meet quality criteria. In total, 88 new Burkholderia protein structures were deposited in the PDB, covering 56 Burkholderia proteins and 49 of the 406 B. thailandensis putative essential genes (a 12.1% gene-to-structure rate).

Interestingly, the underlying rationale for the “ortholog rescue” approach can be verified with the experimental data from seven pairs of ortholog structures solved in the new study. The average overall Cα r.m.s.d. of all pairs was 1.5±0.5Å, indicating that ortholog structures are similar enough to serve as surrogates in drug discovery.

Finally, 25 potential drug targets were identified using three criteria: a lack of close human homologs, membership in an essential metabolic pathway and possession of an essential drug-binding pocket. The authors described five of the most interesting candidates, belonging to synthesis pathways of fatty acids, lipopolysaccharides, siderophores and nucleic acids. As part of the NIAID center's mission, expression clones and proteins were also made available to the infectious disease community for developing new anti-Burkholderia agents.

Wayne Peng


  1. L. Baugh et al. Combining functional and structural genomics to sample the essential Burkholderia structome.
    PLoS ONE. 8, e53851 (2013). doi:10.1371/journal.pone.0053851

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health