The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor-channels takes place in the context of particular models to extract parameters for functional effects. In the often-used co-agonist model, the agonist generating control activity and the potentiator

Bladder, colon, gastric, prostate, and uterine cancers originate in organs surrounded by laminin coated smooth muscle. In human prostate cancer, tumors that are organ-confined, without extracapsular extension (ECE) through muscle, have an overall cancer survival rate of up to 97% as compared to 32% for metastatic disease. Our previous work modeling ECE reported the blocking of tumor invasion by mutation

The most effective tested optogenetic tools available for neuronal silencing are the light-gated anion channel proteins found in the cryptophyte alga Guillardia theta (GtACRs). Molecular mechanisms of GtACRs, including the photointermediates responsible for the open channel state, are of great interest for understanding their exceptional conductance. In this study, the photoreactions of GtACR1 and

4-Amino-4-deoxychorismate synthase (ADCS), a chorismate-utilizing enzyme, is composed of two subunits: PabA and PabB. PabA is a glutamine amidotransferase that hydrolyzes glutamine into glutamate and ammonia. PabB is an aminodeoxychorismate synthase that converts chorismate to 4-amino-4-deoxychorismate (ADC) using the ammonia produced by PabA. ADCS functions under allosteric regulation between PabA

Septins are membrane-associated, GTP-binding proteins that are present in most eukaryotes. They polymerize to play important roles as scaffolds and/or diffusion barriers as part of the cytoskeleton. α-Helical coiled-coil domains are believed to contribute to septin assembly, and those observed in both human SEPT6 and SEPT8 form antiparallel homodimers. These are not compatible with their parallel heterodimeric

Over the past two decades, serial X-ray crystallography has enabled the structure determination of a wide range of proteins. With the advent of X-ray free-electron lasers (XFELs), ever-smaller crystals have yielded high-resolution diffraction and structure determination. A crucial need to continue advancement is the efficient delivery of fragile and micrometre-sized crystals to the X-ray beam intersection

A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of d-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and

Liquid-liquid phase separation (LLPS) inside the cell often results in biological condensates that can critically impact cell homeostasis. Such phase separation events occur in multiple parts of cells, including the cell membranes, where the so-called “lipid raft” hypothesis posits the formation of ordered domains floating in a sea of disordered lipids. The resulting lipid domains often have functional

Caveolins form complexes of various sizes that deform membranes into polyhedral shapes. However, the recent structure of the 8S complex was disk-like with a flat membrane-binding surface. How can a flat complex deform membranes into nonplanar structures? Molecular dynamics simulations revealed that the 8S complex rapidly takes the form of a suction cup. Simulations on implicit membrane vesicles determined

Plasma membrane induced protein folding and conformational transitions play a central role in cellular homeostasis. Several transmembrane proteins are folded in the complex lipid milieu to acquire a specific structure and function. Bacterial pore forming toxins (PFTs) are proteins expressed by a large class of pathogenic bacteria that exploit the plasma membrane environment to efficiently undergo secondary

The activity of many membrane receptors is controlled through their lateral association into dimers or higher order oligomers. While Förster resonance energy transfer (FRET) measurements have been used extensively to characterize the stability of receptor dimers, the utility of FRET in studies of larger oligomers has been limited. Here we introduce an effective equilibrium dissociation constant that

Lysophospholipids (lysoPLs) are crucial metabolites involved in various physiological and pathological cellular processes. Understanding their binding interactions, particularly with human serum albumin (HSA), is essential due to their role in regulating lysoPLs-induced cytotoxicity. However, the precise mechanism of lysoPLs binding to HSA remains elusive. In this study, we employed fluorescence quenching

Fluorescent lipid probes are an invaluable tool for investigating lipid membranes. In particular, localizing particular receptor lipids such as glycosphingolipids within phase-separated membranes is of pivotal interest to understanding the influence of protein-receptor lipid binding on membrane organization. However, fluorescent labeling can readily alter the phase behavior of a lipid membrane because

Since its emergence, the COVID-19 threat has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the

Macromolecular solubility is an important contributor to the driving forces for phase separation. Formally, the driving forces in a binary mixture comprising a macromolecule dissolved in a solvent can be quantified in terms of the saturation concentration, which is the threshold macromolecular concentration above which the mixture separates into coexisting dense and dilute phases. Additionally, the

Chimeric antigen receptor (CAR)-T cells form dynamic immunological synapses with their cancer cell targets. Following a CAR-antigen engagement, the CAR-T synapse forms, matures, and finally disassembles, accompanied by substantial remodeling of cell surface proteins, lipids, and glycans. In this review, we provide perspectives for understanding protein distribution, membrane topology, and force transmission

Early after-depolarizations (EADs) are action potential (AP) repolarization abnormalities that can trigger lethal arrhythmias. Simulations using biophysically-detailed cardiac myocyte models can reveal how model parameters influence the probability of these cellular arrhythmias, however such analyses can pose a huge computational burden. We have previously developed a highly simplified approach in

Piperine is the principal alkaloid present in black pepper and is well-known for its diverse pharmacological effects, including inhibition of different ion channels. Large conductance Ca2+-activated K+ channels (BK) are widely expressed across several tissues and play a vital role in many physiological functions. In this study, we have investigated the pharmacological effects of piperine on various

Writing in Nature, Moger-Reischer et al.1 address this question by studying minimal cells from the Mycoplasma mycoides JCVI-syn3B strain. First, they test how reducing protein coding genes from the approximately 900 found in the original strain (non-minimal cell) to less than 500 in the streamlined strain (minimal cell) affects mutation input. Surprisingly, both strains display similar mutation rates

In January 2024, Nature Structural & Molecular Biology (NSMB) will celebrate the 30th anniversary of publishing its first issue . Though initially launched as Nature Structural Biology in 1994, the journal has since expanded its scope to include all research into the molecular underpinnings of life, with the vision that the broadest insight can be gleaned through a suite of complimentary approaches

The virion protein 40 (VP40) forms the viral matrix, mediates budding, and downregulates viral RNA synthesis in ebolaviruses. In this issue of Structure, Werner et al. present a structure of VP40 from Sudan ebolavirus with a previously unresolved disulfide bridge that enables regulation of VP40 functions via human thioredoxin.

In this issue of Structure, Tettoni et al. present the structure and biochemical characterization of the fission yeast LAMTOR-Gtr complex, which mediates nutrient-dependent control of cell growth. The study reveals specific differences to the homologous human LAMTOR-Rag complex that might represent means of evolutionary adaptation.

Post-translational modifications profoundly influence amyloid assembly. In this issue of Structure, Li et al. unravel the underlying mechanism by which specific lysine acetylation patterns facilitate fibril formation of Tau segments. Their cryo-electron microscopy structure further elucidates how acetyl groups act as stabilizers within the architecture of Tau fibrils.

In this issue of Structure, McCullough et al. describe linker peptides that serve as a “hydrophobic glue” to arrange the domains within the reducing region of a modular polyketide synthase. Comparisons to structural data from other megasynthases identified features that are unique to modular systems.

Abstract not available