Distinct mechanisms of inhibition of Kv2 potassium channels by tetraethylammonium and RY785.

Voltage-gated K channels play central roles in human physiology, both in health and disease. A repertoire of inhibitors that are both potent and specific would therefore be of great value, not only as pharmacological agents but also as research tools. The small molecule RY785 has been described as particularly promising in this regard, as it selectively inhibits channels in the Kv2 subfamily with high potency.

Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse.

Eukaryotic voltage-gated K channels have been extensively studied, but the structural bases for some of their most salient functional features remain to be established. C-type inactivation, for example, is an auto-inhibitory mechanism that confers temporal resolution to their signal-firing activity. In a recent breakthrough, studies of a mutant of Shaker that is prone to inactivate indicated that this process entails a dilation of the selectivity filter, the narrowest part of the ion conduction pathway.

Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175.

Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson's disease. Here, we present a cryoelectron microscopy structure and molecular simulations of TMEM175 bound to 4-aminopyridine (4-AP), the only known small-molecule inhibitor of TMEM175 and a broad K channel inhibitor, as well as a drug approved by the Food and Drug Administration against multiple sclerosis. The structure shows that 4-AP, whose mode of action had not been previously visualized, binds near the center of the ion conduction pathway, in the open state of the channel.

Structure of the Shaker Kv channel and mechanism of slow C-type inactivation.

Voltage-activated potassium (Kv) channels open upon membrane depolarization and proceed to spontaneously inactivate. Inactivation controls neuronal firing rates and serves as a form of short-term memory and is implicated in various human neurological disorders. Here, we use high-resolution cryo-electron microscopy and computer simulations to determine one of the molecular mechanisms underlying this physiologically crucial process.

Bivalent recognition of fatty acyl-CoA by a human integral membrane palmitoyltransferase.

S-acylation, also known as palmitoylation, is the most abundant form of protein lipidation in humans. This reversible posttranslational modification, which targets thousands of proteins, is catalyzed by 23 members of the DHHC family of integral membrane enzymes. DHHC enzymes use fatty acyl-CoA as the ubiquitous fatty acyl donor and become autoacylated at a catalytic cysteine; this intermediate subsequently transfers the fatty acyl group to a cysteine in the target protein.

An Unbound Proline-Rich Signaling Peptide Frequently Samples Conformations in Gaussian Accelerated Molecular Dynamics Simulations.

Disordered proline-rich motifs are common across the proteomes of many species and are often involved in protein-protein interactions. Proline is a unique amino acid due to the covalent bond between the backbone nitrogen and the proline side chain. The resulting five-membered ring allows proline to sample the state about its peptide bond, which other residues cannot do as readily.

Conserved binding site in the N-lobe of prokaryotic MATE transporters suggests a role for Na in ion-coupled drug efflux.

In both prokaryotes and eukaryotes, multidrug and toxic-compound extrusion (MATE) transporters catalyze the efflux of a broad range of cytotoxic compounds, including human-made antibiotics and anticancer drugs. MATEs are secondary-active antiporters, i.e.

Conserved binding site in the N-lobe of prokaryotic MATE transporters suggests a role for Na in ion-coupled drug efflux.

In both prokaryotes and eukaryotes, multidrug and toxic-compound extrusion (MATE) transporters catalyze the efflux of a broad range of cytotoxic compounds, including human-made antibiotics and anticancer drugs. MATEs are secondary-active antiporters, i.e.

A disordered encounter complex is central to the yeast Abp1p SH3 domain binding pathway.

Protein-protein interactions are involved in a wide range of cellular processes. These interactions often involve intrinsically disordered proteins (IDPs) and protein binding domains. However, the details of IDP binding pathways are hard to characterize using experimental approaches, which can rarely capture intermediate states present at low populations.

Structure and Mechanism of DHHC Protein Acyltransferases.

S-acylation, whereby a fatty acid chain is covalently linked to a cysteine residue by a thioester linkage, is the most prevalent kind of lipid modification of proteins. Thousands of proteins are targets of this post-translational modification, which is catalyzed by a family of eukaryotic integral membrane enzymes known as DHHC protein acyltransferases (DHHC-PATs). Our knowledge of the repertoire of S-acylated proteins has been rapidly expanding owing to development of the chemoproteomic techniques.

DHHC20 Palmitoyl-Transferase Reshapes the Membrane to Foster Catalysis.

Cysteine palmitoylation, a form of S-acylation, is a key posttranslational modification in cellular signaling. This type of reversible lipidation occurs in both plasma and organellar membranes, and is catalyzed by a family of integral membrane proteins known as DHHC acyltransferases. The first step in the S-acylation process is the recognition of free acyl coenzyme A (acyl-CoA) from the lipid bilayer.