I mostly post pretty proteins to twitter, but this one deserves more than one image. It’s a membrane pore protein called glutamate-gated chloride channel (GluCl). One of my students pointed it out to me as the target of two drugs to treat filariasis, which refers to a collection of diseases caused by parasitic worms including river blindness and Elephantiasis. They are considered neglected tropical diseases, meaning they’re a big problem in undeveloped countries, but don’t get as much attention from Big Pharma as they warrant because most patients are poor.

GluCl sits in the membrane of worm cells and selectively lets chlorine ions through, depending on the concentration of the molecule glutamate outside the cell. One structure for GluCl is 3RI5. This is in the benign worm C. elegans, but we assume it works similarly in the related disease-causing worms. Click the link and you’ll see this beauty:

Looking down the pore of GluCl. The five "arms" are antibodies, used to stabilize the protein during crystallization.

Sort of looks like a starfish, huh? The grey arms aren’t part of the protein themselves. They’re only there to make it crystallize. A more accurate picture of the protein might be something like this:

A side view of just the GluCl protein. Red and blue patches represent negatively and positively charged portions of the protein. An activator of the protein, Ivermectin, is shown in green. A few other small molecules are also shown in black, which are not important biologically but help stabilize the crystal.

A couple cool things are visible in this picture. First, the region where the protein spans the membrane is clearly visible as a white strip, since since the amino acids within the membrane must be hydrophobic. Second, we can see the drug Ivermectin (green sticks) bound in a pocket near the surface of the membrane. This forces the pore to stay open, flooding worm cells with chlorine and killing them. You can see the pore clearly in the top view:

The large pore in GluCl is visible in this view, which looks down on the protein from outside the cell. At the very bottom, the molecule picrotoxin blocks the channel, preventing chlorine ions from flowing.

The pore is wide at the top, on the outside of the cell, and narrows to a tiny whole at the cytosolic side. In this crystal there are two drugs at work. The Ivermectin is holding the pore in its “open” state, so we can see all the way through the protein. However, it is blocked by another molecule picrotoxin, which “clogs the drain” by binding in the pore.

For more details, read the paper for this structure:

Hibbs, R.E., Gouaux, E. Principles of activation and permeation in an anion-selective Cys-loop receptor. (2011) Nature 474: 54-60
[PubMed]
[DOI]

Share

Leave a Reply

Your email address will not be published. Required fields are marked *