How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?

Tumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 is mutated in nearly 50% of cancers, and mutations can alter the oligomeric state of the protein, having an impact on the biological function of the protein and on cell fate decisions.

Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment.

Somatostatin, an Binder to Aβ Oligomers, Binds to βPFO Tetramers.

Somatostatin (SST14) is strongly related to Alzheimer's disease (AD), as its levels decline during aging, it regulates the proteolytic degradation of the amyloid beta peptide (Aβ), and it binds to Aβ oligomers . Recently, the 3D structure of a membrane-associated β-sheet pore-forming tetramer (βPFO tetramer) has been reported. Here, we show that SST14 binds selectively to the βPFO tetramer with a value of ∼40 μM without binding to monomeric Aβ(1-42).

Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage.

Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimer's disease (AD). Here, we present the three-dimensional structure of an Aβ oligomer formed in a membrane mimicking environment, namely an Aβ(1-42) tetramer, which comprises a six stranded β-sheet core. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment while the edges are hydrophilic and solvent-exposed.

Preparation of a Well-Defined and Stable β-Barrel Pore-Forming Aβ42 Oligomer.

The formation of amyloid-β peptide (Aβ) oligomers at the cellular membrane is considered a crucial process that underlies neurotoxicity in Alzheimer's disease (AD). To obtain structural information on this type of oligomers, we were inspired by membrane protein approaches used to stabilize, characterize, and analyze the function of such proteins. Using these approaches, we developed conditions under which Aβ42, the Aβ variant most strongly linked to the aetiology of AD, assembles into an oligomer that inserts into lipid bilayers as a well-defined pore and adopts a specific structure with characteristics of a β-barrel arrangement.

Unmanned Aerial Vehicles (UAVs) and Artificial Intelligence Revolutionizing Wildlife Monitoring and Conservation.

Surveying threatened and invasive species to obtain accurate population estimates is an important but challenging task that requires a considerable investment in time and resources. Estimates using existing ground-based monitoring techniques, such as camera traps and surveys performed on foot, are known to be resource intensive, potentially inaccurate and imprecise, and difficult to validate. Recent developments in unmanned aerial vehicles (UAV), artificial intelligence and miniaturized thermal imaging systems represent a new opportunity for wildlife experts to inexpensively survey relatively large areas.

Enantiomeric cyclic peptides with different Caco-2 permeability suggest carrier-mediated transport.

Recently, oral absorption of cyclic hexapeptides was improved by N-methylation of their backbone amides. However, the number and position of N-methylations or of solvent exposed NHs did not correlate to intestinal permeability, measured in a Caco-2 model. In this study, we investigate enantiomeric pairs of three polar and two lipophilic peptides to demonstrate the participation of carrier-mediated transporters.

How the substrate D-glutamate drives the catalytic action of Bacillus subtilis glutamate racemase.

Molecular Dynamics simulations with a Molecular Mechanics force field and a quite complete exploration of the QM/MM potential energy surfaces have been performed to study the D-glutamate --> L-glutamate reaction catalyzed by Bacillus subtilis glutamate racemase. The results show that the whole process involves four successive proton transfers that occur in three different steps. The Michaelis complex is already prepared to make the first proton transfer (from Cys74 to Asp10) possible.

New insights into the reaction mechanism catalyzed by the glutamate racemase enzyme: pH titration curves and classical molecular dynamics simulations.

The mechanism of the reactions catalyzed by the pyridoxal-phosphate-independent amino acid racemases and epimerases faces the difficult task of deprotonating a relatively low acidicity proton, the amino acid's alpha-hydrogen, with a relatively poor base, a cysteine. In this work, we propose a mechanism for one of these enzymes, glutamate racemase (MurI), about which many controversies exist, and the roles that its active site residues may play. The titration curves and the pK1/2 values of all of the ionizable residues for different structures leading from reactants to products have been analyzed.

On the ionization state of the substrate in the active site of glutamate racemase. A QM/MM study about the importance of being zwitterionic.

Computer simulations on a QM/MM potential energy surface have been carried out to gain insights into the catalytic mechanism of glutamate racemase (MurI). Understanding such a mechanism is a challenging task from the chemical point of view because it involves the deprotonation of a low acidic proton by a relatively weak base to give a carbanionic intermediate. First, we have examined the dependency of the kinetics and thermodynamics of the racemization process catalyzed by MurI on the ionization state of the substrate (glutamate) main chain.

A Molecular Dynamics Simulation of the Binding Modes of d-Glutamate and d-Glutamine to Glutamate Racemase.

Classical molecular dynamics simulations of the d-Gln/Aquifex pyrophilus MurI and d-Glu/Aquifex pyrophilus MurI complexes have been carried out. Since the active site of the enzyme contains many charged and polar residues, several binding modes are possible. Thus, three very different stable conformations of the substrate analogue d-Gln have been found, and at least three binding modes are possible for the substrate d-Glu.