Tightly bound to DNA proteins: possible universal substrates for intranuclear processes.

Tightly bound to DNA proteins (TBPs) are a protein group that remains attached to DNA after its deproteinization by phenol, chloroform or salting-out. TBP are bound to DNA with covalent phosphotriester or non-covalent ion and hydrogen bonds. They appear to be a vast protein group involved in numerous intranuclear processes. The TBPs fraction co-purified with DNA deproteinized by mild procedures is extremely heterogeneous, tissue and species-specific. The protein fraction co-purified with DNA after harsh deproteinization procedures appears to be formed from few polypeptides common to different species and tissues. Interaction sites between DNA and TBPs depend on the physiological status of the cell. The binding sites of TBPs to DNA do not co-localize with the nuclear matrix attachment regions. We hypothesize that TBPs form a universal substrate for intranuclear processes.

Proteins tightly bound to DNA: new data and old problems.

Proteins tightly bound to DNA (TBP) comprise a group of proteins that remain bound to DNA after usual deproteinization procedures such as salting out and treatment with phenol or chloroform. TBP bind to DNA by covalent phosphotriester and noncovalent ionic and hydrogen bonds. Some TBP are conservative, and they are usually covalently bound to DNA. However, the TBP composition is very diverse and significantly different in different tissues and in different organisms. TBP include transcription factors, enzymes of the ubiquitin-proteasome system, phosphatases, protein kinases, serpins, and proteins of retrotransposons. Their distribution within the genome is nonrandom. However, the DNA primary structure or DNA curvatures do not define the affinity of TBP to DNA. But there are repetitive DNA sequences with which TBP interact more often. The TBP distribution within genes and chromosomes depends on a cell's physiological state, differentiation type, and stage of organism development. TBP do not interact with DNA in the sites of its association with nuclear matrix and most likely they are not components of the latter.

Development of proteo-chemometrics: a novel technology for the analysis of drug-receptor interactions.

A novel method for the analysis of drug receptor interactions has been developed and used to explore mechanisms involved in the binding of 4-piperidyl oxazole antagonists to alpha1a-, alpha1b- and alpha1d-adrenoceptors. The method exploits affinity data for a series of organic chemical compounds binding to wild-type and artificially mutated receptors. The receptor sequences and compounds are assigned predictor variables that are correlated to the measured pharmacological activities using partial least-squares projections to latent structures. The predictor variables consist of one descriptor block derived from the chemical properties of the receptors' primary amino acid sequences and another descriptor block derived from the chemical properties of the organic compounds. The cross-terms generated from the two descriptor blocks are also derived. Using this approach, very sturdy models were generated describing the interactions of the chemical compounds with the receptors. Models are useful to predict binding affinity and receptor subtype selectivity of compounds prior to their synthesis, and may find use in rational drug design. Moreover, models also give quantitative information about the interactions of the amino acids of the receptors with the ligands, thereby giving an insight into the molecular mechanisms involved in ligand binding.