Design of anti-BVDV drug based on common chemical features, their interaction, and scaffolds of TLR8 agonists.

In the absence of an experimental bTLR8 structure, recent studies have called attention to the fact that bTLR8 can also be activated by hTLR7/hTLR8 agonist, such as antiviral imidazoquinoline derivatives of resiquimod (R848) and imiquimod (R837) as well as some guanine nucleotide analogs with a scaffold structure related to the nucleic acids of ssRNA virus. In particular, the known small agonists (namely CL075, CL097 and R848) have been targeted to determine distinguishable deciding factors in complex with dimeric bTLR8-ECDs in comparison to ligand-induced activated hTLR8-ECDs. According to basic knowledge, the deciding eligibility criteria can be subsequently applied in our bTLR8 model to characterize the 3D-arrangement of chemical features (pharmacophore) and to investigate the distinct restrictions affecting species-specificity on dual TLR7/TLR8 small agonists suggested in previous works.

Annular anionic lipids stabilize the integrin αIIbβ3 transmembrane complex.

Cationic membrane-proximal amino acids determine the topology of membrane proteins by interacting with anionic lipids that are restricted to the intracellular membrane leaflet. This mechanism implies that anionic lipids interfere with electrostatic interactions of membrane proteins. The integrin αIIbβ3 transmembrane (TM) complex is stabilized by a membrane-proximal αIIb(Arg(995))-β3(Asp(723)) interaction; here, we examine the influence of anionic lipids on this complex.

Sequence and membrane determinants of the random coil-helix transition of α-synuclein.

A random coil-helix transition underlies the association of the presynaptic protein α-synuclein (αS) with curved vesicle membranes to fold Asp2-Ala89 into a continuous helix. To clarify this transition, we examined αS folding cooperativity, helix nucleation and propagation in relation to membrane stabilization and leakage on diverse small unilamellar vesicles. The sequences centering on Phe4 and Tyr39 initiate lipid interactions and the Phe4 region nucleates the helix irrespective of the order of Ser9-Ala89.

Insight into α-synuclein plasticity and misfolding from differential micelle binding.

Misfolded species of the 140-residue protein α-synuclein (αS) are implicated in the demise of dopaminergic neurons, resulting in fatal neurodegeneration. The intrinsically unstructured protein binds curved synaptic vesicle membranes in helical conformations but misfolds into amyloid fibrils via β-sheet interactions. Breaks in helical αS conformation may offer a pathway to transition from helical to sheet conformation.

Construction of covalent membrane protein complexes and high-throughput selection of membrane mimics.

The association of transmembrane (TM) helices underlies membrane protein structure and folding. Structural studies of TM complexes are limited by complex stability and the often time-consuming selection of suitable membrane mimics. Here, methodology for the efficient, preparative scale construction of covalent TM complexes and the concomitant high-throughput selection of membrane mimics is introduced.

The clustering and spatial arrangement of beta-sheet sequence, but not order, govern alpha-synuclein fibrillogenesis.

The intrinsically unstructured protein alpha-synuclein (aS) is prone to misfold into cytotoxic beta-sheet-rich oligomers and amyloid fibrils that underlie the pathogenesis of Lewy body diseases such as Parkinson's disease. An important, recognized fibrillogenesis parameter is amino acid content, whereas the influence of amino acid sequence distribution is not as well understood. The fibril core of aS encompasses five regions of high beta-sheet propensity, termed beta1-beta5.

Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein.

Infection by the mosquito-borne dengue virus causes dengue fever and the sometimes fatal dengue hemorrhagic fever. The increasing number of dengue infections per year suggests that the virus is becoming more virulent and its transmission is expanding. Nevertheless, no effective treatment for dengue infection currently exists.

Solution conformation of alphaA-conotoxin EIVA, a potent neuromuscular nicotinic acetylcholine receptor antagonist from Conus ermineus.

We report the solution three-dimensional structure of an alphaA-conotoxin EIVA determined by nuclear magnetic resonance spectroscopy and restrained molecular dynamics. The alphaA-conotoxin EIVA consists of 30 amino acids representing the largest peptide among the alpha/alphaA-family conotoxins discovered so far and targets the neuromuscular nicotinic acetylcholine receptor with high affinity. alphaA-Conotoxin EIVA consists of three distinct structural domains.