Conformational change in protein-ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-m...

Human neurodegenerative diseases arise from a wide array of genetic and environmental factors. Despite the diversity in etiology, many of these diseases are considered "conformational" in nature, characterized by the accumulation of pathological, misfolded proteins. These misfolded proteins can induce cellular stress by overloading the proteolytic machinery, ultimately resulting in the accumula...

Recent reports give strong support to the idea that amyloid fibril formation and the subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. In this review, recent findings are surveyed to illustrate that protein fibrillogenesis requires a partially folded conformation. This amyloidogenic conformation is relatively unf...

The influenza A M2 protein forms a proton channel for virus infection and mediates virus assembly and budding. While extensive structural information is known about the transmembrane helix and an adjacent amphipathic helix, the conformation of the N-terminal ectodomain and the C-terminal cytoplasmic tail remains largely unknown. Using two-dimensional (2D) magic-angle-spinning solid-state NMR, w...

background and objective: familial hypercholesterolemia (fh) is an autosomal trait, which is caused by mutations in low density lipoprotein receptor (ldlr) gene. fh penetrance is about 100% and worldwide prevalence for heterozygous subjects is almost 1 in 500 and for homozygous 1 in 1,000,000. the patients are at risk of premature coronary heart disease (chd) due to defective ldlr and hence cho...

We present a series of conformational search calculations on the aggregation of short peptide fragments that form fibrils similar to those seen in many protein mis-folding diseases. The proteins were represented by a face-centered cubic lattice model with the conformational energies calculated using the Miyazawa-Jernigan potential. The searches were performed using algorithms based on the Metro...

In conformational diseases, native protein conformers convert to pathological intermediates that polymerize. Structural characterization of these key intermediates is challenging. They are unstable and minimally populated in dynamic equilibria that may be perturbed by many analytical techniques. We have characterized a forme fruste deficiency variant of α(1)-antitrypsin (Lys154Asn) that forms p...

G protein-coupled receptors (GPCRs) have important functionality in cell signaling processes by external affects such as light, smell, taste, and hormones. The conformational changes in structures of GPCR’s play vital role in signaling processes. The understanding of conformational changes is useful to determine basis of certain diseases that are related to malfunctioning of these proteins. The...

The morpheein model of allosteric regulation can be applied as a novel approach to the discovery of small molecule allosteric modulators of protein function. Morpheeins are homo-oligomeric proteins where, under physiological conditions, the oligomer can dissociate, the dissociated units can change conformation, and the altered conformational state can reassociate to a structurally and functiona...

Pyruvate carboxylase (PC) is a conserved multifunctional enzyme linked to important metabolic diseases. PC homotetramer is arranged in two layers with two opposing monomers per layer. Cryo-EM explores the conformational variability of PC in the presence of different substrates. The results demonstrate that the biotin-carboxyl carrier protein (BCCP) domain localizes near the biotin carboxylase (...