Deep Brain Stimulation beyond the Clinic: Navigating the Future of Parkinson's and Alzheimer's Disease Therapy.

Deep brain stimulation (DBS) is a surgical procedure that uses electrical neuromodulation to target specific regions of the brain, showing potential in the treatment of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Despite similarities in disease pathology, DBS is currently only approved for use in PD patients, with limited literature on its effectiveness in AD. While DBS has shown promise in ameliorating brain circuits in PD, further research is needed to determine the optimal parameters for DBS and address any potential side effects.

Virtual Reality Therapy for Depression and Mood in Long-Term Care Facilities.

Virtual reality (VR) describes a family of technologies which immerse users in sensorily-stimulating virtual environments. Such technologies have increasingly found applications in the treatment of neurological and mental health disorders. Depression, anxiety, and other mood abnormalities are of concern in the growing older population-especially those who reside in long-term care facilities (LTCFs).

Molecular dynamics simulations of an engineered T4 lysozyme exclude helix to sheet transition, and provide insights into long distance, intra-protein switchable motion.

An engineered variant of T4 lysozyme serves as a model for studying induced remote conformational changes in a full protein context. The design involves a duplicated surface helix, flanked by two loops, that switches between two different conformations spanning about 20 Å. Molecular dynamics simulations of the engineered protein, up to 1 μs, rule out α-helix to β-sheet transitions within the duplicated helix as suggested by others.

The NS4A Cofactor Dependent Enhancement of HCV NS3 Protease Activity Correlates with a 4D Geometrical Measure of the Catalytic Triad Region.

We are developing a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active site of HCV NS3 proteases, in relation to their catalytic activity. In our previous work, the 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) yielded divergent, gradual and genotype-dependent, 4D conformational instability measures, which strongly correlate with the known disparate catalytic activities among genotypes. Here, the correlation of our 4D geometrical measure is extended to intra-genotypic alterations in NS3 protease activity, due to sequence variations in the NS4A activating cofactor.

Bioactivation of luteolin by tyrosinase selectively inhibits glutathione S-transferase.

Glutathione S-transferase (GST) plays a significant role in the metabolism and detoxification of drugs used in treatment of melanoma, resulting in a decrease in drug efficacy. Tyrosinase is an abundant enzyme found in melanoma. In this study, we used a tyrosinase targeted approach to selectively inhibit GST.

Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.

The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity.

Structure-based mechanism for Na(+)/melibiose symport by MelB.

The bacterial melibiose permease (MelB) belongs to the glycoside-pentoside-hexuronide:cation symporter family, a part of the major facilitator superfamily (MFS). Structural information regarding glycoside-pentoside-hexuronide:cation symporter family transporters and other Na(+)-coupled permeases within MFS has been lacking, although a wealth of biochemical and biophysical data are available. Here we present the three-dimensional crystal structures of Salmonella typhimurium MelBSt in two conformations, representing an outward partially occluded and an outward inactive state of MelBSt.

Over-expression and characterization of NS3 and NS5A of Hepatitis C virus genotype 3a.

Background: Hepatitis C virus (HCV) is a common and leading cause for liver cirrhosis and hepatocellular carcinoma. Current therapies to treat HCV infection are shown to be partially effective and poorly tolerated. Therefore, ample efforts are underway to rationally design therapies targeting the HCV non-structural proteins.

A 3D structural model and dynamics of hepatitis C virus NS3/4A protease (genotype 4a, strain ED43) suggest conformational instability of the catalytic triad: implications in catalysis and drug resistivity.

Egypt has the highest prevalence of hepatitis C virus (HCV) infection worldwide with a frequency of 15%. More than 90% of these infections are due to genotype 4, and the subtype 4a (HCV-4a) predominates. Moreover, due to the increased mobility of people, HCV-4a has recently spread to several European countries.

The metabolic bioactivation of caffeic acid phenethyl ester (CAPE) mediated by tyrosinase selectively inhibits glutathione S-transferase.

Glutathione S-transferase (GST) and multidrug resistance-associated proteins (MRPs) play major roles in drug resistance in melanoma. In this study, we investigated caffeic acid phenethyl ester (CAPE) as a selective GST inhibitor in the presence of tyrosinase, which is abundant in melanoma cells. Tyrosinase bioactivates CAPE to an o-quinone, which reacts with glutathione to form CAPE-SG conjugate.

A 3D structure model of the melibiose permease of Escherichia coli represents a distinctive fold for Na+ symporters.

The melibiose permease of Escherichia coli (MelB) catalyzes the coupled stoichiometric symport of a galactoside with a cation (either Na(+), Li(+), or H(+)), using free energy from the downhill translocation of one cosubstrate to catalyze the accumulation of the other. Here, we present a 3D structure model of MelB threaded through a crystal structure of the lactose permease of E. coli (LacY), manually adjusted, and energetically minimized.

X-ray beam stabilization at BL-17A, the protein microcrystallography beamline of the Photon Factory.

BL-17A is a new structural biology beamline at the Photon Factory, Japan. The high-brilliance beam, derived from the new short-gap undulator (SGU#17), allows for unique protein crystallographic experiments such as data collection from microcrystals and structural determination using softer X-rays. However, microcrystal experiments require robust beam stability during data collection and minor fluctuations could not be ignored.

Miranda cargo-binding domain forms an elongated coiled-coil homodimer in solution: implications for asymmetric cell division in Drosophila.

Miranda is a multidomain adaptor protein involved in neuroblast asymmetric division in Drosophila melanogaster. The central domain of Miranda is necessary for cargo binding of the neural transcription factor Prospero, the Prospero-mRNA carrier Staufen, and the tumor suppressor Brat. Here, we report the first solution structure of Miranda central "cargo-binding" domain (residues 460-660) using small-angle X-ray scattering.

Guanidinium derivatives bind preferentially and trigger long-distance conformational changes in an engineered T4 lysozyme.

The binding of guanidinium ion has been shown to promote a large-scale translation of a tandemly duplicated helix in an engineered mutant of T4 lysozyme. The guanidinium ion acts as a surrogate for the guanidino group of an arginine side chain. Here we determine whether methyl- and ethylguanidinium provide better mimics.

Structural basis of Prospero-DNA interaction: implications for transcription regulation in developing cells.

The crystal structure of a complex between the novel homeodomain of the neural transcription factor Prospero and DNA shows that the invariant residues Lys1290, Asn1294, and Asp1297 make specific contacts with the noncanonical DNA binding site. The overall structure includes the homeodomain and the adjacent Prospero domain and confirms that they act as a single structural unit, a Homeo-Prospero domain. The Prospero domain facilitates the proper alignment of the protein on the DNA.

Use of sequence duplication to engineer a ligand-triggered, long-distance molecular switch in T4 lysozyme.

We have designed a molecular switch in a T4 lysozyme construct that controls a large-scale translation of a duplicated helix. As shown by crystal structures of the construct with the switch on and off, the conformational change is triggered by the binding of a ligand (guanidinium ion) to a site that in the wild-type protein was occupied by the guanidino head group of an Arg. In the design template, a duplicated helix is flanked by two loop regions of different stabilities.

The putative catalytic bases have, at most, an accessory role in the mechanism of arginine kinase.

Arginine kinase is a member of the phosphagen kinase family that includes creatine kinase and likely shares a common reaction mechanism in catalyzing the buffering of cellular ATP energy levels. Abstraction of a proton from the substrate guanidinium by a catalytic base has long been thought to be an early mechanistic step. The structure of arginine kinase as a transition state analog complex (Zhou, G.

Induced fit in guanidino kinases--comparison of substrate-free and transition state analog structures of arginine kinase.

Arginine kinase (AK) is a member of the guanidino kinase family that plays an important role in buffering ATP concentration in cells with high and fluctuating energy demands. The AK specifically catalyzes the reversible phosphoryl transfer between ATP and arginine. We have determined the crystal structure of AK from the horseshoe crab (Limulus polyphemus) in its open (substrate-free) form.

Refinement of the arginine kinase transition-state analogue complex at 1.2 A resolution: mechanistic insights.

The three-dimensional crystal structure of an arginine kinase transition-state analogue complex has been refined at 1.2 A resolution, with an overall R factor of 12.3%.