A special issue of JGP celebrates the 2018 Symposium of the Society of General Physiologists, where diversity and world-class science went hand in hand.
Navarro et al discuss new work using the gating-modifier toxin GxTx to investigate the molecular mechanism of Kv2.1 channel gating.
Robertson reflects on a new study showing how ensemble-biased metadynamics can be used to interpret BetP protein dynamics data.
Rhomboid proteases are membrane-integrated enzymes that hydrolyze peptide bonds in the transmembrane domains of protein substrates. Gaffney and Hong experimentally determine interaction energies between active site residues to reveal weak coupling, which may explain the slow proteolysis mediated by GlpG.
Guangxitoxin-1E (GxTx) is a peptide from tarantula venom that binds to Kv2.1 voltage sensors and inhibits channel activity. Tilley et al. investigate the allosteric mechanism of GxTx and show that it stabilizes the resting state of voltage sensors and limits opportunities for the pore to open.
The mechanosensitive channel NOMPC comprises a pore-forming transmembrane domain plus four helical ankyrin repeats that extend into the cytoplasm. Using computational approaches, Argudo et al. show that compression of the ankyrin chains imparts a rotational torque on a putative gating element.
The connexin26 human mutation N14K disrupts cytosolic intersubunit interactions and promotes channel opening
The N14K mutation in the N-terminal domain of connexin26 produces gain-of-function hemichannels. Valdez Capuccino et al. reveal that the mutation disrupts intersubunit interactions between the N terminus and the second transmembrane domain–cytoplasmic loop transition.
Antidepressants alter the function of their target membrane proteins. They also alter lipid bilayer properties and thereby affect other membrane proteins. Kapoor et al. use gramicidin A channels to probe how antidepressants affect the lipid bilayer, providing a new mechanism for their off-target effects.
Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds
ASCT2 is a transporter that exchanges neutral amino acids such as glutamine across the cell membrane, an essential process for rapidly growing cells, including cancerous ones. Ndaru et al. report the synthesis and characterization of a novel class of inhibitors useful for studying this transporter.
Methods and Approaches
Although high-resolution structures are now available for many ion-coupled, or secondary, transporters, the mechanisms by which coupling is achieved remain to be determined. Lolkema and Slotboom derive new mathematical models that can be used to analyze transport data and determine kinetic mechanisms.
Interpretation of spectroscopic data using molecular simulations for the secondary active transporter BetP
Use of spectroscopic techniques to complement structural data and enhance mechanistic understanding of membrane proteins is often complicated by experimental discrepancies. Leone et al. address this challenge by applying an advanced simulation methodology to the interpretation of spectroscopic data for the transporter protein BetP.