Structural biology relies on several powerful techniques, but these tend to be limited in their ability to characterize protein fluctuations and mobility. Over-reliance on structural approaches can lead to omission of critical information regarding biological function. Currently there is a need for complementary biophysical methods to visualize these mobile aspects of protein function. Here we review

Using data from the UK Biobank the researchers analyzed the rare variants in the protein coding region in the genomes of 106,973 women. They identified rare variants that disrupt the function of nine genes that are associated with ANM. Four of these were already known while five were linked to ANM for the first time. Three of the five new genes (PALB2, ETAA1 and HROB) are involved in the DNA damage

The ability of biological systems to withstand and recover from various disruptions, such as spontaneous genetic mutations and environmental damage, largely relies on intricate feedback mechanisms. We theoretically study a mechanical response of an epithelial tissue facing damage in the form of a circular wound. Our model describes a feedback loop between the generation of active forces in the actomyosin

In this issue of Structure, Shaw et al.1 visualize the PI4KA-TTC7B-FAM126A-calcineurin complex by combining cryo-EM, HDX-MS, and AlphaFold3, and reveal a dual interaction of calcineurin with PI4KA and FAM126A. This work promotes our understanding of calcineurin-regulated PI4KA activity and paves the way for further exploration of the roles of PI4KA in the plasma membrane.

G protein-coupled receptors (GPCRs) orchestrate many physiological functions and are a crucial target in drug discovery. Adhesion GPCRs (aGPCRs), the second largest family within this superfamily, are promising yet underexplored targets for treating various diseases, including obesity, psychiatric disorders, and cancer. However, the receptors’ unique and complex structure and miscellaneous interactions

In this issue of Structure, Dey et al.1 employ single-molecule FRET to map the conformational trajectory of Omicron spikes during fusion, revealing a transition from pre-fusion to post-fusion through two intermediates. This study highlights the roles of acidic environments, Ca2+, and receptors in promoting SARS-CoV-2 cell entry.

The enzymatically regioselective catalyzed incorporation of cysteine sulfoxide into histidine generates physiologically important antioxidants such as ergothioneine and ovothiol. In this issue of Structure, Ireland et al.1 report the crystal structure of EgtB-IV, which provides insights into the convergent evolution of sulfoxide synthase.

Phosphorylation of ubiquitin and the ubiquitin-like domain of Parkin, mediated by the kinase PINK1, is essential for the liberation of the E3 ligase from its autoinhibited state. In this issue of Structure, Lenka et al.1 provide the structural basis for the specificity and stronger Parkin activation by phospho-NEDD8 compared to phospho-ubiquitin.

The ability of cells to sense and respond to mechanical forces is crucial for navigating their environment and interacting with neighboring cells. Myosin II and cortexillin I form complexes known as contractility kits (CKs) in the cytosol, which facilitate a cytoskeletal response by accumulating locally at the site of inflicted stress. Here, we present a computational model for mechanoresponsiveness

Synaptic vesicle clusters or pools are functionally important constituents of chemical synapses. In the so-called reserve and the active pools, neurotransmitter-loaded synaptic vesicles (SVs) are stored and conditioned for fusion with the synaptic membrane and subsequent neurotransmitter release during synaptic activity. Vesicle clusters can be considered as so-called membraneless compartments, which

T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) interactions that result in T cell activation are complex and have been distinguished by their equilibrium affinity and kinetic profiles. While prior affinity-based models can successfully predict meaningful TCR-pMHC interactions in many cases, they occasionally fail at identifying TCR-pMHC interactions with low binding affinity

Three analogue solvatochromic probes, Laurdan, Prodan, and Acdan, are extensively used in the study of biological sciences. Their locations in lipid membranes vary greatly in depth, and their fluorescence responds to their surrounding environment based on their corresponding locations in the membrane. Utilizing the fluorescence lifetimes (τ) and emission peaks (λ) acquired from time-resolved emission

All living cells vibrate depending on metabolism. It has been hypothesized that vibrations are unique for a given phenotype and thereby suitable to diagnose cancer type and stage and to pre-assess the effectiveness of pharmaceutical treatments in real time. However, cells exhibit highly variable vibrational signals, can be subject to environmental noise, and may be challenging to differentiate, having

Cardiac ventricular myocyte action potential dynamics are regulated by intricate and nonlinear interactions between the cell transmembrane potential and ionic currents and concentrations. Present technology limits the ability to measure transmembrane potential and multiple ionic currents simultaneously, which narrows the scope of experiments to provide a complete snapshot of the cardiac myocyte state

Experimental studies of collective dynamics in lipid bilayers have been challenging due to the energy resolution required to observe these low-energy phonon-like modes. However, inelastic x-ray scattering (IXS) measurements—a technique for probing vibrations in soft and biological materials—are now possible with sub-meV resolution, permitting direct observation of low-energy, phonon-like modes in lipid

Solutions of the intrinsically disordered, low-complexity domain of the FUS protein (FUS-LC) undergo liquid-liquid phase separation (LLPS) below a temperature TLLPS. To investigate whether local conformational distributions are detectably different in the homogeneous (i.e., single-phase) and phase-separated states of FUS-LC, we performed solid-state NMR (ssNMR) measurements on solutions that were frozen

Cellular membranes exhibit a huge diversity of lipids and membrane proteins that differ in their properties and chemical structure. Cells organize these molecules into distinct membrane compartments characterized by specific lipid profiles and hydrophobic thicknesses of the respective domains. If a hydrophobic mismatch occurs between a membrane protein and the surrounding lipids, there can be functional

(Structure 32, 1–16; November 7, 2024)

The dissipation of electrochemical gradients through ion channels plays a central role in biology. Herein we use voltage-responsive kinetic models of ion channels to explore how electrical and chemical potentials differentially influence ion transport properties. These models demonstrate how electrically driven flux is greater than the Nernstian equivalent chemically driven flux yet still perfectly

The process of biological fate decision regulated by gene regulatory networks involves numerous complex dynamical interactions among many components. Mathematical modeling typically employed ordinary differential equations and steady-state analysis, which has yielded valuable quantitative insights. However, stable states predicted by theoretical models often fail to capture transient or metastable

Single-molecule force spectroscopy (SMFS) techniques play a pivotal role in unraveling the mechanics and conformational transitions of biological macromolecules under external forces. Among these techniques, multiplexed magnetic tweezers (MT) are particularly well suited to probe very small forces, ≤1 pN, critical for studying noncovalent interactions and regulatory conformational changes at the single-molecule

(Structure 32, 1–15; December 5, 2024)

For protein crystals in which more than two thirds of the volume is occupied by solvent, the featureless nature of the solvent region often generates a constraint that is powerful enough to allow direct phasing of X-ray diffraction data. Practical implementation relies on the use of iterative projection algorithms with good global convergence properties to solve the difficult nonconvex phase-retrieval

Pollution from plastics is a global problem that threatens the biosphere for a host of reasons, including the time scale that it takes for most plastics to degrade. Biodegradation is an ideal solution for remediating bioplastic waste as it does not require the high temperatures necessary for thermal degradation and does not introduce additional pollutants into the environment. Numerous organisms can

In homoeostasis, the shape and sessility of untransformed epithelial cells are intricately linked together. Variations of this relationship in migrating cancer cells as they encounter different microenvironments are as yet ill understood. Here, we explore the interdependency of such traits in two morphologically distinct invasive ovarian cancer cell lines (OVCAR-3 and SK-OV-3) under mechanically variant