Structural biology

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

Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer.

Abstract: The Solute Carrier 1A (SLC1A) family includes two major mammalian transport systems—the alanine serine cysteine transporters (ASCT1-2) and the human glutamate transporters otherwise known as the excitatory amino acid transporters (EAAT1-5). The EAATs play a critical role in maintaining low synaptic concentrations of the major excitatory neurotransmitter glutamate, and hence they have been widely researched over a number of years. More recently, the neutral amino acid exchanger, ASCT2 has garnered attention for its important role in cancer biology and potential as a molecular target for cancer therapy. The nature of this role is still being explored, and several classes of ASCT2 inhibitors have been developed. However none have reached sufficient potency or selectivity for clinical use. Despite their distinct functions in biology, the members of the SLC1A family display structural and functional similarity. Since 2004, available structures of the archaeal homologues GltPh and GltTk have elucidated mechanisms of transport and inhibition common to the family. The recent determination of EAAT1 and ASCT2 structures may be of assistance in future efforts to design efficacious ASCT2 inhibitors. This review will focus on ASCT2, the present state of knowledge on its roles in tumour biology, and how structural biology is being used to progress the development of inhibitors.

The Structural Biology of Bcl-xL

Abstract: Interactions between the pro-survival and pro-apoptotic members of the Bcl-2 family of proteins dictate whether a cell lives or dies. Much of our knowledge of the molecular details of these interactions has come from biochemical and structural studies on the pro-survival protein Bcl-xL. The first high-resolution structure of any Bcl-2 family member was of Bcl-xL, which revealed the conserved topology amongst all family members. Subsequent structures of Bcl-xL complexes with pro-apoptotic ligands demonstrated the general features of all pro-survival:pro-apoptotic complexes. Structural studies involving Bcl-xL were also the basis for the discovery of the first small-molecule pro-survival protein inhibitors, leading ultimately to the development of a new class of drugs now successfully used for cancer treatment in the clinic. This article will review our current knowledge of the structural biology of Bcl-xL and how this has impacted our understanding of the molecular details of the intrinsic apoptotic pathway.

Stabilization of RNA oligomers through reverse micelle encapsulation.

Abstract: The cellular milieu is rich in diversity of both simple and complex molecules and is also quite crowded By contrast, typical sample concentrations employed for in vitro investigation of biophysics and structural biology make use of purified macromolecules in simple buffer systems at concentrations that range from micromolar to millimolar Although this formulation has proven to be compatible with a wide range of biological and structural studies, it is quite different from the relatively crowded conditions typically found within cells The importance of these crowding effects for proteins has been recognized for some time, but the equivalent analysis is underexplored in nucleic acids Encapsulation with surfactant-based reverse micelles has emerged as an effective biophysical tool, allowing study of the influence of ionic strength, pH, hydration, and crowding on biologically active macromolecules over a wide range of conditions We have encapsulated an oligonucleotide model of TAR RNA from HIV and the 5' stem loop oligonucleotide of the U4 snRNA Observation of imino (1)H resonances is an established method for evaluating the stability of nucleic acid oligonucleotides, implying the presence of stacked, hydrogen bonded base pairs Inspection of (1)H NMR spectra of the RNA molecules reveals that the intensity of several of the imino resonances increases upon encapsulation Additional resonances not observed in spectra of the oligonucleotides free in solution support the suggestion that the molecules have gained stability These results indicate that RNA oligonucleotides may acquire significant stability in the presence of cellular levels of crowding

Membrane re-modelling by BAR domain superfamily proteins via molecular and non-molecular factors.

Abstract: Lipid membranes are structural components of cell surfaces and intracellular organelles. Alterations in lipid membrane shape are accompanied by numerous cellular functions, including endocytosis, intracellular transport, and cell migration. Proteins containing Bin–Amphiphysin–Rvs (BAR) domains (BAR proteins) are unique, because their structures correspond to the membrane curvature, that is, the shape of the lipid membrane. BAR proteins present at high concentration determine the shape of the membrane, because BAR domain oligomers function as scaffolds that mould the membrane. BAR proteins co-operate with various molecular and non-molecular factors. The molecular factors include cytoskeletal proteins such as the regulators of actin filaments and the membrane scission protein dynamin. Lipid composition, including saturated or unsaturated fatty acid tails of phospholipids, also affects the ability of BAR proteins to mould the membrane. Non-molecular factors include the external physical forces applied to the membrane, such as tension and friction. In this mini-review, we will discuss how the BAR proteins orchestrate membrane dynamics together with various molecular and non-molecular factors.