PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons
E-Collection

Related Articles
Design and Evolution: Molecular Sleuthing Reveals Drug Selectivity
June 2015
Families in Gene Neighborhoods
June 2015
Ryanodine Receptor
April 2015
CCR5 and HIV Infection
January 2015
Drug Targets: Bile Acids in Motion
September 2014
Drug Targets: S1R's Ligands and Partners
September 2014
P2Y Receptors and Blood Clotting
September 2014
Bacterial CDI Toxins
June 2014
Glucagon Receptor
April 2014
Viroporins
March 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Design and Discovery: Virtual Drug Screening
January 2014
Cancer Networks: IFI16-mediated p53 Activation
November 2013
G Proteins and Cancer
November 2013
Drug Discovery: Antidepressant Potential of 6-NQ SERT Inhibitors
October 2013
Drug Discovery: Finding Druggable Targets
October 2013
Drug Discovery: Identifying Dynamic Networks by CONTACT
October 2013
Drug Discovery: Modeling NET Interactions
October 2013
Membrane Proteome: GPCR Substrate Recognition and Functional Selectivity
August 2013
Infectious Diseases: Determining the Essential Structome
May 2013
NDM-1 and Antibiotics
May 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Cytochrome Oxidase
November 2012
Membrane Proteome: The ABCs of Transport
November 2012
Bacterial Phosphotransferase System
October 2012
Regulatory insights
September 2012
Solute Channels
September 2012
Pocket changes
July 2012
Receptor bias
July 2012
Anthrax Stealth Siderophores
June 2012
G Protein-Coupled Receptors
May 2012
Substrate specificity sleuths
April 2012
Reading out regioselectivity
December 2011
Superbugs and Antibiotic Resistance
December 2011
Terminal activation
December 2011
A change to resistance
November 2011
Docking and rolling
October 2011
Breaking down the defenses
September 2011
A2A Adenosine Receptor
May 2011
Cell wall recycler
May 2011
Subtly different
March 2011
CXCR4
January 2011
Subtle shifts
January 2011
ABA receptor diversity
November 2010
COX inhibition: Naproxen by proxy
November 2010
Zinc Transporter ZntB
July 2010
Peptidoglycan binding: Calcium-free killing
June 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Antibiotics and Ribosome Function
March 2010
Safer Alzheimer's drugs?
March 2010
Anthrax evasion tactics
September 2009
GPCR subunits: Separate but not equal
September 2009
Antibiotic target
August 2009
Salicylic Acid Binding Protein 2
August 2009
Lysostaphin
July 2009
Tackling influenza
June 2009
Bacterial Leucine Transporter, LeuT
May 2009
Anthrax stealth molecule
March 2009
Drug targets to aim for
February 2009
High-energy storage system
February 2009
Transporter mechanism in sight
February 2009
Scavenger Decapping Enzyme DcpS
November 2008
Blocking AmtB
September 2008

Research Themes Drug discovery

Bacterial CDI Toxins

SBKB [doi:10.3942/psi_sgkb/fm_2014_6]
Featured System - June 2014
Short description: PSI researchers have solved the structures of several potent bacterial toxins, along with their antidotes.

Evolution is driven by competition, as organisms fight for available resources. In particularly competitive situations, this can lead to evolutionary arms races, with competitors developing ever-more-powerful weapons to gain an advantage. This is particularly apparent in bacteria, which build a bewildering variety of toxic peptides and proteins to deploy against their neighbors.

Killing on Contact

A new class of bacterial toxins, termed CDI for contact-dependent growth inhibition, was discovered a decade ago. As the name implies, these toxins require close proximity with their targets, and the system includes several proteins that work together to kill competitors on contact. One component forms a gateway in the membrane of the attacking cell, which is essential for the display of the toxic component on the cell surface. The toxic component is a large protein with a very long connector and a toxin domain. The connector includes a segment that binds to receptors on the target cell, where the toxin domain is cleaved, forces its way inside the cell, and wreaks havoc.

Terrible Toxins

PSI researchers at UC4CDI have recently solved the structures of the toxin domains of CDI proteins from several different types of bacteria. As discovered by these researchers, the toxins chop up nucleic acids in the target, but the targets are quite different in each: one breaks a key bond in a transfer RNA, one targets ribosomal RNA, and one is a nonspecific nuclease that, with the help of a zinc ion, avidly destroys all the DNA in sight. The one shown here is from the bacterium Enterobacter cloacae, from PDB entry 4ntq. The structure includes the toxic domain of the protein, shown here in pink, with several active site amino acids shown with ball-and-stick representation. Once inside cells, this protein will make a specific cut in ribosomal RNA, ultimately shutting down protein synthesis and killing the cell. The protein bound to the toxin, shown here in blue, is an inhibitor made by the attacking bacterium for self-protection.


The Antidote

These bacteria must have a way to protect themselves from collateral damage by their own weapons, so they each build a specific inhibitor protein that blocks the toxin until it is deployed against their enemies. Two examples from different bacteria are shown here, from PDB entries 4g6u and 4g6v, with the toxin in pink and the inhibitor in blue. These two inhibitors use entirely different modes of action to block the toxin: the one on the right binds squarely in the middle of the active site, but the one on the left binds on the side of the toxin. These different modes make sense, though: each bacterium needs to have its own secret method of inhibition, otherwise their target bacteria would be able to use their own inhibitors for protection.


Inhibitors in Action

The CDI toxin from Escherichia coli (PDB entry 4g6u) is inhibited in an interesting way: the inhibitor grips a hairpin loop (shown in red) out of the toxin. The way this blocks the nuclease action of the toxin is still a matter of conjecture, since it leaves the active site totally exposed. It may block the approach of the target DNA, or it may distort the toxin in a way that inactivates it. The hairpin loop binds in a form-fitting slot in the inhibitor, completing a ring of beta sheets that together form a beta barrel (shown in turquoise). To look at this interaction more closely, the JSmol tab below displays an interactive JSmol.

CdiA Toxin and Inhibitor (PDB entry 4g6u)

The inhibitor of the CdiA toxin of Escherichia coli traps a beta hairpin from toxin inside a stable beta barrel. In this JSMol, the toxin is shown in red with the beta hairpin in brighter red and the active site amino acids in pink, and the inhibitor protein is in blue with the beta barrel in brighter turquoise. Use the buttons to take a closer look and to change the representation.

References

  1. Beck, C. M. et al. CdiA from Enterobacter cloacae delivers a toxic ribosomal RNase into target bacteria. Structure 22, 1-22 (2014).

  2. Morse, R. P. et al. Structural basis of toxicity and immunity in contact-dependent growth inhibition (CDI) systems. PNAS 109, 21480-21485 (2012).

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