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Research Themes Drug discovery

Solute Channels

SBKB [doi:10.3942/psi_sgkb/fm_2012_9]
Featured System - September 2012
Short description: Cells maintain a steady traffic of small molecules across their membranes.

Cells maintain a steady traffic of small molecules across their membranes. They use two different overall approaches. In some cases, they actively transport molecules across, using dynamic proteins that grab the molecule on one side, shift in shape, and then release the molecule on the other side. In other cases, such as the urea transporter shown here (PDB entry 4ezc), transport is more passive, with molecules filing through a channel across the membrane. In both cases, it is essential to keep the transport controlled and specific, so that only the proper molecules are allowed to cross. Channels are particularly tricky, because they need to let their cargo pass through, but without allowing protons or ions to leak across the membrane at the same time.

Channeling Potassium

The structure of the KscA potassium channel (PDB entry 1bl8) first revealed the basic methods used by channels that selectively transport soluble molecules. KscA is composed of four identical chains that surround a central channel. The channel has a narrow "selectivity filter" at the center, composed of a ring of amino acids that are finely tuned to fit potassium ions, but not other types of ions. Potassium ions, stripped of their normal shell of water molecules, file one-by-one through the filter to cross the membrane.

Structural Similarities

PSI researchers at NYCOMPS have explored many other channels, revealing a common structural solution to their challenging task. Several examples are included here, all viewed from the "top" so you can see through the channel: the potassium channel TrkH (PDB entry 3pjz), the urea transporter UT-B (PDB entry 4ezc), and the hydrosulfide ion channel FNT3 (PDB entry 3tdo). Each forms a complex composed of several chains, but unlike the KscA channel, the functional pore is not created between several chains, but instead, a channel is formed through the middle of each subunit (the large holes in the middle of the UT-B and FNT3 complexes are presumably blocked with lipids or other molecules). Like KscA, the channels rely on selectivity filters at the center to ensure that only the proper molecules pass. The channels also have a specialized collection of amino acids at the entrance and exit, which match the chemical features of the molecule that they transport.

Being Selective

The urea transporter (PDB entry 4ezd) uses a variety of chemical tricks to recognize its target molecule. At the entrance and exit to the UT-B pore, there is an "oxygen ladder" composed of three aligned oxygen atoms. These are perfectly placed for forming hydrogen bonds with urea. In addition, several large hydrophobic amino acids form a urea-shaped slot that fits the molecule perfectly. At the center of the pore, of a ring of hydrophobic amino acids (shown here in green), which is only wide enough for urea to pass, strips all the water molecules from urea before it can pass through. Based on theoretical studies, PSI researchers have proposed that this desolvation is the energy-limiting step of passage through the pore. To explore these features in more detail, click on the JSmol tab for an interactive Jmol.

Urea Transporter UT-B (PDB entry 4ezd)

The urea transporter has several structural features, collectively known as the selectivity filter, that control the flow of urea through the central pore. At the center of the pore is a constriction surrounded by hydrophobic amino acids (shown in green) that make a narrow opening just large enough for urea, but not surrounding waters. On either side of the constriction, urea is recognized and positioned by a ladder of oxygen atoms (shown in red) and several flanking hydrophobic amino acids (in

References

  1. Czyzewski, B. K. & Wang, D.-W. Identification and characterization of a bacterial hydrosulfide ion channel. Nature 483, 494-498 (2012).

  2. Levin, E. J., et al. Structure and permeation mechanism of the mammalian urea transporter. Proc. Natl. Acad. Sci. USA 109, 11194-11199 (2012).

  3. Cao, Y., et al. Crystal structure of a potassium ion transporter, TrkH. Nature 471, 336-341 (2011).

  4. Doyle, D. A., et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69-77 (1998).

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