Structural biology

About: Structural biology is a research topic. Over the lifetime, 2206 publications have been published within this topic receiving 126070 citations.

Structure-based analysis of CysZ-mediated cellular uptake of sulfate.

Abstract: Sulfur, most abundantly found in the environment as sulfate (SO42-), is an essential element in metabolites required by all living cells, including amino acids, co-factors and vitamins. However, current understanding of the cellular delivery of SO42- at the molecular level is limited. CysZ has been described as a SO42- permease, but its sequence family is without known structural precedent. Based on crystallographic structure information, SO42- binding and flux experiments, we provide insight into the molecular mechanism of CysZ-mediated translocation of SO42- across membranes. CysZ structures from three different bacterial species display a hitherto unknown fold and have subunits organized with inverted transmembrane topology. CysZ from Pseudomonas denitrificans assembles as a trimer of antiparallel dimers and the CysZ structures from two other species recapitulate dimers from this assembly. Mutational studies highlight the functional relevance of conserved CysZ residues.

Exploring designability of electrostatic complementarity at an antigen-antibody interface directed by mutagenesis, biophysical analysis, and molecular dynamics simulations.

Abstract: Antibodies protect organisms from a huge variety of foreign antigens. Antibody diversity originates from both genetic and structural levels. Antigen recognition relies on complementarity between antigen-antibody interfaces. Recent methodological advances in structural biology and the accompanying rapid increase of the number of crystal structures of proteins have enabled atomic-level manipulation of protein structures to effect alterations in function. In this study, we explored the designability of electrostatic complementarity at an antigen-antibody interface on the basis of a crystal structure of the complex. We designed several variants with altered charged residues at the interface and characterized the designed variants by surface plasmon resonance, circular dichroism, differential scanning calorimetry, and molecular dynamics simulations. Both successes and failures of the structure-based design are discussed. The variants that compensate electrostatic interactions can restore the interface complementarity, enabling the cognate antigen-antibody binding. Retrospectively, we also show that these mutational effects could be predicted by the simulations. Our study demonstrates the importance of charged residues on the physical properties of this antigen-antibody interaction and suggests that computational approaches can facilitate design of antibodies that recognize a weakly immunogenic antigen.

Bridge: A Graph-Based Algorithm to Analyze Dynamic H-Bond Networks in Membrane Proteins.

Abstract: Membrane proteins that function as transporters or receptors must communicate with both sides of the lipid bilayer in which they sit. This long distance communication enables transporters to move protons or other ions and small molecules across the bilayer and receptors to transmit an external signal to the cell. Hydrogen bonds, hydrogen-bond networks, and lipid-protein interactions are essential for the motions and functioning of the membrane protein and, consequently, of outmost interest to structural biology and numerical simulations. We present here Bridge, an algorithm tailored for efficient analyses of hydrogen-bond networks in membrane transporter and receptor proteins. For channelrhodopsin, a membrane protein whose functioning involves proton-transfer reactions, Bridge identifies extensive networks of protein-water hydrogen bonds and an unanticipated network that can bridge transiently two proton donors across a distance of ∼20 A. Graphs of the protein hydrogen bonds reveal rapid propagation of structural changes within hydrogen-bond networks of mutant transporters and identify protein groups potentially important for the proton transfer activity. The algorithm is made available as a plugin for PyMol.

Free-energy landscapes of protein domain movements upon ligand binding.

Abstract: The conformation and functions of proteins are closely linked, and many proteins undergo conformational changes upon ligand binding. The X-ray crystallographic studies have revealed conformational differences in proteins between the liganded and unliganded states. Currently, the conformational transitions that originate in the ligand binding are explained on the basis of two representative models, the induced-fit and preexisting equilibrium dynamics models. However, the actual dynamics of the proteins remain ambiguous. Though these two models are the extreme ones, it is important to understand the difference between these two, particularly in structural biology and medicinal chemistry studies. Here, we clarified the difference in the mechanisms responsible for the conformational changes induced in two proteins upon ligand binding by examining computationally determined free-energy profiles of the apo- and holoproteins. The lysine/arginine/ornithine-binding protein and maltose/maltodextrin-binding protein ...