BJ Articles Ahead of Print

In this perspective, we discuss the physiological roles of Na and K channels, emphasizing the importance of the K channel for cellular homeostasis in animal cells and of Na and K channels for cellular signalling. We consider the structural basis of Na and K channel gating in light of recent structural and electrophysiological findings.

Ongoing COVID-19 pandemic caused by new coronavirus, SARS-CoV-2, calls for urgent developments of vaccines and antiviral drugs. The spike protein of SARS-CoV-2 (S-protein), which consists of trimeric polypeptide chains with glycosylated residues on the surface, triggers the virus entry into a host cell. Extensive structural and functional studies on this protein have rapidly advanced our understanding of the S-protein structure at atomic resolutions, while most of structural studies overlook the effect of glycans attached to S-protein on the conformational stability and functional motions between the inactive Down and the active Up forms.

The human ether-a-go-go-related gene (hERG) encodes the voltage gated potassium channel (KCNH2 or Kv11.1, commonly known as hERG). This channel plays a pivotal role in the stability of phase 3 repolarization of the cardiac action potential. Although a high-resolution cryo-EM structure is available for its depolarized (open) state, the structure surprisingly did not feature many functionally important interactions established by previous biochemical and electrophysiology experiments. Using Molecular Dynamics Flexible Fitting (MDFF), we refined the structure and recovered the missing functionally relevant salt bridges in hERG in its depolarized state.

The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Due to these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid to improve the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 Å resolution using cryo-electron microscopy (cryo-EM).

This work builds upon the record-breaking speed and generous immediate release of new experimental 3D structures of the SARS-CoV-2 proteins and complexes, which are crucial to downstream vaccine and drug development. We have surveyed those structures to catch the occasional errors that could be significant for those important uses and for which we were able to provide demonstrably higher-accuracy corrections. This process relied on new validation and correction methods such as CaBLAM and ISOLDE, not yet in routine use.

Peptides that self-assemble into nanometer-sized pores in lipid bilayers could have utility in a variety of biotechnological and clinical applications if we can understand their physical chemical properties and learn to control their membrane selectivity. To empower such control, we have used synthetic molecular evolution to identify the pHD peptides, a family of peptides that assemble into macromolecule-sized pores in membranes at low peptide concentration, but only at pH < ∼6. Further advancements will also require better selectivity for specific membranes.

Neutral lipids (NLs) are apolar oil molecules synthesized in the endoplasmic reticulum (ER) bilayer upon diverse biological stimuli. NLs synthesized are released in the hydrophobic core of the bilayer. At a critical concentration, NLs condense by phase separation and nucleate a lipid droplet (LD). After an LD forms, a fraction of NLs can be present in the bilayer but at a concentration below that of the nucleation. Here, we study whether and how the accumulation of NLs alters a lipid bilayer's mechanical properties.

We discuss recent observations of polymorphic chromatin packaging at the oligo-nucleosomal level and compare them with computer simulations. Our computations reveal two topologically different families of two-start 30-nm fiber conformations distinguished by the linker length, L: fibers with L ≈ 10n and L ≈ 10n+5 bp have DNA linking numbers per nucleosome of ΔLk ≈ –1.5 and –1.0, respectively (where n is a natural number). While fibers with ΔLk ≈ –1.5 were observed earlier, the topoisomer with ΔLk ≈ –1.0 is novel.

Innate immune responses, such as cell death and inflammatory signaling, are typically switch-like in nature. They also involve “prion-like” self-templating polymerization of one or more signaling proteins into massive macromolecular assemblies known as signalosomes. Despite the wealth of atomic-resolution structural information on signalosomes, how the constituent polymers nucleate, and whether the switch-like nature of that event at the molecular scale relates to the digital nature of innate immune signaling at the cellular scale, remains unknown.

The cell membrane is an inhomogeneous system composed of phospholipids, sterols, carbohydrates, and proteins that can be directly attached to underlying cytoskeleton. The protein linkers between the membrane and the cytoskeleton are believed to have a profound effect on the mechanical properties of the cell membrane and its ability to reshape. Here we investigate the role of membrane-cortex linkers on the extrusion of membrane tubes using computer simulations and experiments. In simulations we find that the force for tube extrusion has a non-linear dependence on the density of membrane-cortex attachments: at a wide range of low and intermediate linker densities the force is not significantly influenced by the presence of the membrane-cortex attachments and resembles that of the bare membrane.

Single giant unilamellar vesicles (GUVs) rupture spontaneously from their salt-laden suspension onto solid surfaces. At hydrophobic surfaces, the GUVs rupture via a recurrent, bouncing ball rhythm. During each contact, the GUVs, rendered tense by the substrate interactions, porate and spread a molecularly transformed motif of a monomolecular layer on the hydrophobic surface from the point of contact in a symmetric manner. The competition from pore closure however limits the spreading and produces a daughter vesicle, which re-engages with the substrate.