PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

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
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
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
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


SBKB [doi:10.3942/psi_sgkb/fm_2014_3]
Featured System - March 2014
Short description: PSI researchers have determined the structures of several viral pore-forming proteins, revealing common functional features.

Viruses always seem to find streamlined ways of doing things. Their enzymes are often multifunctional and more compact than their cellular counterparts, and overlapping genes allow them to pack a lot of genetic information into a small space. They have also found a very parsimonious way of creating membrane channels. These simple channels, termed viroporins, are stripped to the bare minimum, with just enough molecular machinery to perform their membrane-spanning function.

Funneling Calcium

The p7 protein of the hepatitis C virus, shown here from PDB entry 2m6x, is a perfect example. PSI researchers at MPSbyNMR have recently solved the structure of the channel using NMR spectroscopy. The structure reveals a compact funnel-shaped pore composed of six identical chains, each only 63 amino acids long. The funnel constricts down to a ring of asparagine amino acids, which together form a selectivity ring that may favor the passage of calcium ions over other ions like sodium or potassium.

Elusive Functions

Viroporins are essential for efficient infectivity, but their exact functional roles are still a subject of study and debate. They may be important for disrupting the normal ion balance of the cell, especially as new viruses are exiting from the infected cell. They may also be important for allowing passage of ions into and out of the virus, so that it can sense when it is inside a cell and ready to release its genome. In addition, they often also act as scaffolds, interacting with other cellular and viral proteins and holding them near to the membrane. All of these hypotheses are the subject of current research, to try to uncover the varied roles these viroporins are playing in different viruses.

Viroporin Diversity

Membrane-spanning channels have been discovered in many viruses. Three examples are shown here. The hepatitis C p7 channel is shown at the bottom, composed of six identical chains. Two even more compact proteins are shown at the top. The M2 protein of influenza (PDB entry 2rlf) is composed of four identical chains, each forming a single alpha helix that passes through the membrane. It is selective for the passage of protons through the membrane. The membrane-spanning portion of Vpu from HIV-1 (PDB entry 1pi7) is composed of five identical chains, and forms a weakly-selective ion pore.

Inhibiting Viroporins

Given their essential function in viral infectivity, researchers have searched for inhibitors of viroporins to use as antiviral drugs. Amantadine compounds were an early success. They are shaped like a little ball that lodges in the channel, as seen in this structure of influenza M2 protein (PDB entry 2ljc). Unfortunately, viruses have rapidly developed resistance to these drugs, so they are not effective with most strains. To explore this structure in more detail, click on the JSmol tab for an interactive Jmol. (Best viewed in Firofox)

Influenza Virus M2 (PDB entry 2ljc)

The M2 protein from influenza virus is composed of four short protein chains that form a channel through membranes. Use the buttons to display the inhibitor rimantadine, which blocks the channel, and two key amino acids that define the characteristics of the channel: a histidine (in turquoise) that transports protons through the channel, and a tryptophan (magenta) that forms a gate that blocks larger molecules from passing. (best viewed in Firofox - if low res image loads, click on it to load hi-res image)


  1. OuYang, B. & Chou, J. J. The minimalist architectures of viroporins and their therapeutic implications. Biochim. Biophys. Acta (2013)

  2. OuYang, B., et al. Unusual architecture of the p7 channel from hepatitis C virus. Nature 498, 521-525.

  3. Nieva, J. L., Madan, V. & Carrasco, L. Viroporins: structure and biological functions. Nature Rev. Microbio. 10, 563-574 (2012).

  4. Pielak, R. M., Oxenoid, K. & Chou, J. J. Structural investigation of rimantadine inhibition of the AM2-BM2 chimera channel of influenza viruses. Structure 19, 1655- 1663 (2011).

  5. Schnell, J. R. & Chou, J. J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451, 591-595 (2008).

  6. Park, S. H. et al. Structure of the channel-forming trans-membrane domain of the virus protein "u" (Vpu) from HIV-1. J. Mol. Biol. 333, 409-424 (2003).

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