The MD model proved to be a reliable tool for selecting suitable excipients for the solubilization of docetaxel.

The peripheral benzodiazepine receptor, implicated in the transport of cholesterol from the outer to the inner mitochondrial membrane, is predicted by hydropathy analysis to feature five membrane-spanning domains, with the amino terminus within the mitochondrial periplasm and the carboxyl terminus in the external cytoplasm. We have tested these structural predictions directly by immunodetection of c-Myc-tagged peripheral benzodiazepine receptor on intact yeast mitochondria and by specific labeling in yeast membranes of cysteine residues introduced by site-directed mutagenesis. The combined results support the model originally proposed with some minor but important modifications. The theoretical model predicted relatively short ␣-helical domains, only long enough to span a phospholipid monolayer, whereas the results presented here would support a model with extended ␣-helices sufficiently long to span an entire membrane bilayer, with concomitant shorter loop and tail regions.The peripheral (or mitochondrial) benzodiazepine receptor (PBR) 1 possesses a benzodiazepine binding site that is clearly distinct from the modulator site of the neurotransmitter ␥-aminobutyric acid receptor. PBR is present in most, if not all, tissues and is particularly abundant in the outer membrane of mitochondria. PBR has been suggested to be required for the transport of cholesterol from the outer to the inner mitochondrial membrane where steroid biosynthesis takes place (1). The receptor also appears to play a key role in modulating mitochondrial electrophysiology, which suggests its implication in the side effects of benzodiazepine pharmacology (for recent review, see Ref. 2). An outer membrane sensory protein of the proteobacterium Rhodobacter sphaeroides has recently been shown (3) to have a close structural and functional relationship with the PBR, supporting the hypothesis that mammalian mitochondria are of photosynthetic bacterial origin. The identification of an 18-kDa protein in human tissues (4) followed by the isolation of the corresponding cDNA (5) allowed us to produce recombinant human PBR in Saccharyomyces cerevisiae (6, 7), an organism normally devoid of binding sites for PBR ligands, thus opening up new avenues for the study of PBR structure-activity relationships.Hydrophobicity analysis of the amino acid sequences of the rat (8) (rPBR), murine (9) (mPBR), bovine (10) (bPBR), and human (5) (hPBR), together with the positive inside rule (11) led to a two-dimensional membrane topological model comprising an intramitochondrial short amino-terminal region and five putative amphipathic ␣-helices linked by hydrophilic loops leading to an extramitochondrial carboxyl-terminal tail (12). A similar pentahelix topology has been found at 2.2-Å resolution for a crystallized apolipoprotein (13) and from gene fusion studies of the cytochrome c terminal oxidase complex of Escherichia coli (14). A three-dimensional model for PBR was proposed and studied using molecular dynamics simulations (12). It was concluded from this model that t...

Low-molecular weight self-assembling organogelators may allow the preparation of novel in situ-forming hydrophobic implants.

With a simple solvent free-process, it was possible to produce long-circulating LN of controlled sizes. Such LN could prove useful for the passive delivery of lipophilic anticancer drugs to solid tumors.

The peripheral type benzodiazepine receptor (PBR) binds benzodiazepines such as RO5-4864 and isoquinoline carboxamide derivatives such as PK11195. This receptor includes an M r 18,000 isoquinoline-binding subunit predominantly located in mitochondrial membranes. This protein has been found to copurify with two other mitochondrial proteins, namely the outer membrane voltage-dependent anion channel (VDAC), also known as mitochondrial porin, and the inner membrane adenine nucleotide carrier. In vitro reconstitution experiments suggested that the PBR was a multimeric complex in which the isoquinoline binding site was on the M r 18,000 subunit, denoted pk18, whereas the benzodiazepine binding site required the association of this subunit with VDAC to be expressed. Untransformed cells of the yeast Saccharomyces cerevisiae are devoid of specific binding sites for isoquinolines and benzodiazepines, whereas yeast cells transformed with a pk18-expressing vector exhibit RO5-4864 and PK11195 binding sites that are pharmacologically identical to those of the PBR. To clarify the role of VDAC and of the adenine nucleotide carrier, if any, in the constitution of the benzodiazepine binding site, yeast host strains were constructed in which the corresponding genes had been knocked out. Mitochondria prepared from pk18-producing cells devoid of either VDAC or adenine nucleotide carrier exhibit both benzodiazepine and isoquinoline carboxamide binding sites with little or no change in the K d values as compared with the wild-type background. These results rule out the contention that VDAC is indispensable for establishing the benzodiazepine binding site and are in agreement with the hypothesis that the M r 18,000 subunit carries both the isoquinoline carboxamide and benzodiazepine binding domains.