ABSTRACT
We developed a computer program for the calculation and display of the difference distance matrices (DDMs) of macromolecules that has the ability to compare multiple structures simultaneously. To demonstrate its use, a data set of atoms for superimposition of the HIV-1 reverse transcriptase enzyme was defined using the coordinates for the 21 available crystal structures of this enzyme and its complexes. The DDM technique for superimposition data set generation allows selection of atoms that are invariant in all structures, is free from user bias, and represents the most accurate and precise method of producing such subsets. Comparison of this technique was made against other published methods of generating superimposition data sets, and it was found that significant differences in magnitude and trends of atom movements are observed depending on which data set was used.
Subject(s)
Computer Graphics , HIV Reverse Transcriptase/chemistry , Mathematical Computing , Crystallography, X-Ray , HIV Reverse Transcriptase/antagonists & inhibitors , Ligands , Motion , PliabilityABSTRACT
Corticotropin-releasing hormone (CRH) is an endogenous 41-amino acid peptide involved in a wide ranging series of systems including the brain, the coordination of the body's overall response to stress, and more recently as a crucial initiator in the onset of labor, also known as the placental clock. Although more physiological data on CRH is emerging shedding more light on the processes involved and their integration, the mode of action of the hormone and the postulated binding site(s) remain unknown. Recently, a number of small-molecular-weight ligands have emerged as potent antagonists but, as therapeutics, suffer from a lack of solubility. Additionally, despite a number of exhaustively large patents, the lack of structural diversity with these antagonists has enabled little scope for comprehensive and wide ranging studies into the structure of the binding sites of this hormone. As part of a program investigating new, structurally diverse antagonists and agonists of CRH, we have developed a preliminary pharmacophore based on the known small-molecular-weight ligands as an initial step in our program. This pharmacophore was validated by comparison with some of the compounds we postulated to be active.
Subject(s)
Corticotropin-Releasing Hormone/antagonists & inhibitors , Adrenocorticotropic Hormone/metabolism , Animals , Binding Sites , Cell Line , Corticotropin-Releasing Hormone/chemistry , Ligands , Mice , Models, Molecular , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
In this report, we describe protein damage by a series of metal complexes that mediate the formation of hydroxyl radical. The protein targets used are bovine serum albumin (BSA) and carboxypeptidase A (CPA). BSA contains several electrostatic, hydrogen bonding and hydrophobic binding sites for potential interaction with the metal complexes, and CPA contains a specific phenylalanine binding site. The data presented in this study show that aromatic side chain damage and backbone cleavage occur to similar extents with all the complexes. Reasonable levels of backbone cleavage specificity can be attained with relatively few recognition elements, despite the fact that a diffusible radical mediates cleavage. Incorporation of additional recognition elements can enlarge the set of cleavage sites. We show that the chemical environment of the cleavage reaction, manipulated by using different buffers, can dramatically affect the outcome of the cleavage reaction. Our work suggests that backbone cleavage site is determined by three factors: the binding sites of the metal complexes, the role of reactive sites on the protein backbone, and the influence of the chemical environment on the reaction.
Subject(s)
Amino Acids/chemistry , Carboxypeptidases/metabolism , Hydroxyl Radical/pharmacology , Metals/pharmacology , Serum Albumin, Bovine/metabolism , Binding Sites/physiology , Buffers , Carboxypeptidases A , Copper/pharmacology , Electrophoresis, Polyacrylamide Gel , Iron/pharmacology , Kinetics , Mass Spectrometry , Phenylalanine/chemistry , Spectrophotometry , TemperatureABSTRACT
Today, we are increasingly aware of the important role the right ventricle plays in maintaining hemodynamic stability. When the right ventricle fails, added stress is placed on the cardiovascular system. This article focuses on patients with perioperative right heart failure and the associated complex nursing care that is needed to manage these patients. Three major nursing diagnoses are reviewed, including decreased cardiac output, impaired gas exchange, and high risk for ineffective family coping.
