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PubMed2006

Structural themes and variations in protein kinase A as seen by small-angle scattering and neutron contrast variation.

Using small-angle solution scattering and neutron contrast variation, we have studied the structure of the multi-subunit protein kinase A. We have gained insights into how nature can take a set of common structural domains (or themes) and modulate their interactions via sequence variations and second messenger mediated signaling to affect enzyme activity and receptor binding important for targeting this multi-function enzyme to specific sub-cellular locations. These studies demonstrate the power of neutron contrast variation to expand our knowledge of the dynamic supra-molecular structures that carry out biological function.

Binding Sites↗
PubMed1999

Computed tomography of humans and bowed stringed instruments. Some interesting similarities.

We have used computed tomography to evaluate bowed stringed instruments and have noted interesting analogies with CT scans of humans. In humans, CT commonly detects a broad range of normal anatomic variations. Similarly, CT of violins and cellos demonstrates a wide range of normal structural variations. CT, often used to detect infections in humans, also detects defects from wood infestations. In humans, the unrelenting effect of gravity causes deformity of the demineralized spine. In old stringed instruments, plastic deformity of wood results from unrelenting string pressure. Trauma causes bone fractures in humans and wood fractures in bowed stringed instruments, and repairing fractures in both humans and stringed instruments requires various splitting devices. In summary, CT provides the physician and the luthier with a unique, noninvasive tool that can characterize the broad range of normal structures, pathological conditions, and repair.

Fractures, Bone↗
PubMed2004

Allelic variations in gene expression.

PURPOSE OF REVIEW: Genetic variants determine phenotypic variability. Many genetic studies suggest that protein structural variations predispose the population to more than 1000 different hereditary diseases. Unfortunately, despite the study of genetic polymorphisms for many decades, the milder phenotypic variations believed to account for most human physical and behavioral differences and underlying the most common human genetic diseases (including cancers) cannot be accounted for easily by these variations in the protein coding sequences. Thus, it has been hypothesized that the study of natural differential expression presenting within and among populations may enhance understanding of human phenotypic variation. RECENT FINDINGS: During the last year, reports identifying variations in gene expression in different organisms and finding subtle changes of gene expression associated with common genetic disease have pointed to variations in gene expression as playing a central role in molecular evolution and human disease. Advances in the functional analysis of gene regulatory networks-in particular, new methods for distinguishing cis-acting components from trans-acting factors-have provided the impetus for these discoveries. SUMMARY: This review represents current knowledge about allelic variation in gene expression and its increasingly important role in understanding the genotype-phenotype relation. Characterization of these allelic variations may open largely uncharted territory in genomics for biomedical researchers and may eventually lead to the discovery of the causative genes of common hereditary diseases and their mechanism of action.

Alleles↗
PubMed2025

Genetic Differentiation is Constrained to Chromosomal Inversions and Putative Centromeres in Locally Adapted Populations With Higher Gene Flow.

The impact of genome structure on adaptation is a growing focus in evolutionary biology, revealing an important role for structural variation and recombination landscapes in shaping genetic diversity across genomes and among populations. This is particularly relevant when local adaptation occurs despite gene flow, where clustering of differentiated loci can maintain locally adapted variants by reducing recombination between them. However, the limited genomic resources for nonmodel species, including reference genomes and recombination maps, have constrained our understanding of these patterns. In this study, we leverage the Atlantic silverside-a nonmodel fish with extensive local adaptation across a steep latitudinal gradient-as an ideal system to explore how genome structure influences adaptation under varying levels of gene flow, using a newly available reference genome and multiple recombination maps. Analyzing 168 genomes from four populations, we found a continuum of genome-wide differentiation increasing from south to north, reflecting higher connectivity among southern populations and reduced gene flow at northern latitudes. With increasing gene flow, the number and clustering of FST outlier loci also increased, with differentiated loci found exclusively within large haploblocks harboring inversions and smaller peaks overlapping putative centromeric regions. Notably, sequence divergence was only evident in inversions, supporting their role in adaptive divergence with gene flow, whereas centromeric regions appeared differentiated because of low recombination and diversity, with no indication of elevated divergence. Our results support the hypothesis that clustered genomic architectures evolve with high gene flow and enhance our understanding of how inversions and centromeres are linked to different evolutionary processes.

Gene Flow↗
PubMed1989

Sequence-dependent variations in the 31P NMR spectra and backbone torsional angles of wild-type and mutant Lac operator fragments.

Assignment of the 31P resonances of a series of six sequenced-related tetradecamer DNA duplexes, d(TGTGAGCGCTCACA)2, d(TATGAGCGCTCATA)2, d(TCTGAGCGCTCAGA)2, d(TGTGTGCGCACACA)2, d(TGTGACGCGTCACA)2 and d(CACAGTATACTGTG)2, related to the lac operator DNA sequence was determined either by site-specific 17O labeling of the phosphoryl groups or by two-dimensional 1H-31P pure absorption phase constant time (PAC) heteronuclear correlation spectroscopy. J(H3'-P) coupling constants for each of the phosphates of the tetradecamers were obtained from 1H-31P J-resolved selective proton flip 2D spectra. By use of a modified Karplus relationship the C4'-C3'-O3'-P torsional angles (epsilon) were obtained. Comparison of the 31P chemical shifts and J(H3'-P) coupling constants of these sequences has allowed greater insight into those various factors responsible for 31P chemical shift variations in oligonucleotides and provided an important probe of the sequence-dependent structural variation of the deoxyribose phosphate backbone of DNA in solution. These sequence-specific variations in the conformation of the DNA sugar phosphate backbone of various lac operator DNA sequences can possibly explain the sequence-specific recognition of DNA by DNA binding proteins, as mediated through direct contacts between the phosphates and the protein.

Base Sequence↗
PubMed1994

A new approach to the design of sigma-2-selective ligands: synthesis and evaluation of N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine-related polyamines at sigma-1 and sigma-2 receptor subtypes.

A series of polyamines based on the high affinity sigma receptor ligand N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) were developed and evaluated for their binding characteristics at sigma-1 and sigma-2 receptor subtypes. The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at sigma receptors. As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes. Although additional nitrogen atoms resulted in decreased affinity at sigma-1 and sigma-2 subtypes, an increase in selectivity for sigma-2 subtypes was evident; the parent 3 showed greater selectivity for sigma-1 subtypes. Internitrogen spacings had a large effect on binding affinity and subtype selectivity. For example, the difference between N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)-N,N'- dimethylethylenediamine (8) [K(i) = 29.9 nM at sigma-1 receptor and 18.3 nM at sigma-2 receptor] to N-[3-(1-pyrrolidinyl)propyl]-N'-(3,4-dichlorobenzyl)- N,N'-dimethylethylenediamine (10) [K(i) = 1.49 nM at sigma-1 receptor and 12.1 nM at sigma-2 receptor] illustrates the importance of internitrogen spacing. Triamines 11 and 13 [Ki(sigma-2)/K(i)(sigma-1) = 0.19 and 0.10, respectively] containing the N-N-N-Ar spacings 3-3-2 and 4-4-2, proved to be the most sigma-2 subtype selective of the 15 polyamines examined in this study. The N-N-N spacings appear to be an important factor in their sigma-2 subtype selectivity. These compounds will serve as templates in the design of still further sigma-2 subtype selective ligands. The pyrrolidine ring (present in most of the polyamines tested in this series) proved to be an important recognition site for sigma receptor binding activity. Furthermore, alkyl substitution also appears to be important since the stripped down polyamines N-[2-(3,4-dichlorophenyl)ethyl]ethylenediamine (15) and N1-[2-(3,4-dichlorophenyl)ethyl]diethylenetriamine (16) exhibited relatively low binding affinity.

Animals↗
PubMed2002

Probing the role of glutamic acid 139 of Anabaena ferredoxin-NADP+ reductase in the interaction with substrates.

The role of the negative charge of the E139 side-chain of Anabaena Ferredoxin-NADP+ reductase (FNR) in steering appropriate docking with its substrates ferredoxin, flavodoxin and NADP+/H, that leads to efficient electron transfer (ET) is analysed by characterization of several E139 FNR mutants. Replacement of E139 affects the interaction with the different FNR substrates in very different ways. Thus, while E139 does not appear to be involved in the processes of binding and ET between FNR and NADP+/H, the nature and the conformation of the residue at position 139 of Anabaena FNR modulates the precise enzyme interaction with the protein carriers ferredoxin (Fd) and flavodoxin (Fld). Introduction of the shorter aspartic acid side-chain at position 139 produces an enzyme that interacts more weakly with both ET proteins. Moreover, the removal of the charge, as in the E139Q mutant, or the charge-reversal mutation, as in E139K FNR, apparently enhances additional interaction modes of the enzyme with Fd, and reduces the possible orientations with Fld to more productive and stronger ones. Hence, removal of the negative charge at position 139 of Anabaena FNR produces a deleterious effect in its ET reactions with Fd whereas it appears to enhance the ET processes with Fld. Significantly, a large structural variation is observed for the E139 side-chain conformer in different FNR structures, including the E139K mutant. In this case, a positive potential region replaces a negative one in the wild-type enzyme. Our observations further confirm the contribution of both attractive and repulsive interactions in achieving the optimal orientation for efficient ET between FNR and its protein carriers.

Anabaena↗
PubMed2005

Optimized modified topliss method: a tool for quantitative structure-activity relationship studies.

The structural variation of lead compounds often includes the variation of substituents at a particular site. A common difficulty, in quantitative structure-activity relationship (QSAR) studies, is to select the best substituents to obtain, with a minimum number of experiments, a major change in some impor. tant properties of the molecule. To improve a proposed modified Topliss method, 187 different substituted compounds belonging to 70 series were studied. A single linear regression was carried out between the experimental activity of each series of compounds and the molecular structure parameters pi, sigma, Es and MR, along with some combinations of them, in order to select the best substituents for constructing the "reduced" correlation. This selection considered the scaled smallest residue average of the substituent, the number of times that the substituent is inserted in the 70 series and its quadrant in the Craig graph. The results obtained in this study with this simple method showed a good predictive capacity when compared with the multiple regression analysis, using the Hansch method.

Algorithms↗
PubMed2005

Protein secondary structure assignment revisited: a detailed analysis of different assignment methods.

BACKGROUND: A number of methods are now available to perform automatic assignment of periodic secondary structures from atomic coordinates, based on different characteristics of the secondary structures. In general these methods exhibit a broad consensus as to the location of most helix and strand core segments in protein structures. However the termini of the segments are often ill-defined and it is difficult to decide unambiguously which residues at the edge of the segments have to be included. In addition, there is a "twilight zone" where secondary structure segments depart significantly from the idealized models of Pauling and Corey. For these segments, one has to decide whether the observed structural variations are merely distorsions or whether they constitute a break in the secondary structure. METHODS: To address these problems, we have developed a method for secondary structure assignment, called KAKSI. Assignments made by KAKSI are compared with assignments given by DSSP, STRIDE, XTLSSTR, PSEA and SECSTR, as well as secondary structures found in PDB files, on 4 datasets (X-ray structures with different resolution range, NMR structures). RESULTS: A detailed comparison of KAKSI assignments with those of STRIDE and PSEA reveals that KAKSI assigns slightly longer helices and strands than STRIDE in case of one-to-one correspondence between the segments. However, KAKSI tends also to favor the assignment of several short helices when STRIDE and PSEA assign longer, kinked, helices. Helices assigned by KAKSI have geometrical characteristics close to those described in the PDB. They are more linear than helices assigned by other methods. The same tendency to split long segments is observed for strands, although less systematically. We present a number of cases of secondary structure assignments that illustrate this behavior. CONCLUSION: Our method provides valuable assignments which favor the regularity of secondary structure segments.

Algorithms↗
PubMed1975

Variability in Acanthocephalus parksidei Amin, 1974 (Acanthocephala: Echinorhynchidae).

Acanthocephalus parksidei Amin, 1974, was recently described from 11 species of Wisconsin fishes. Considerable variation was observed in this acanthocephalan's body size, number and arrangement of proboscis hook, size of hooks, proboscis, proboscis receptacle, lemnisci, embryos, testes, and cement glands, and number of the latter two. Most of these variations were related to worm sex and age as well as host species. Structural variations in the shape and lobation of lemnisci, abnormalities in hooks and body wall, and changes associated with monorchidism in males were noted. The significance of the erection of this new taxon in relation to the taxonomic criteria applied to acanthocephalan species is discussed.

Acanthocephala↗
PubMed2006

Conserved conformation of RecA protein after executing the DNA strand-exchange reaction. A site-specific linear dichroism structure study.

RecA protein and its eukaryotic homologue Rad51 protein catalyzes the DNA strand exchange, which is a key reaction of homologous recombination. At the initial step of the reaction, RecA proteins form a helical filament on a single-stranded DNA (ssDNA). Binding of double-stranded DNA (dsDNA) to the filament triggers the homology search; as homology is found, the exchange of strands occurs, and the displaced DNA is released. These are the principal steps of genetic recombination; however, despite many years of extensive study of RecA activities, the details of the mechanism are still obscure. A high-resolution structure of the active nucleoprotein filament could provide information to help understand this process. Using a linear dichroism polarized-light spectroscopy technique, in combination with protein engineering (the site-specific linear dichroism method), we have previously studied the arrangement of RecA in complex with ssDNA. In the present study, we have used this approach to search for structural variations of RecA at the atomic level as the DNA in the complex is changed from ssDNA to dsDNA. The structural data of the RecA-dsDNA filament are found to be very similar to the data previously obtained for the RecA-ssDNA complex, indicating that the overall orientation and also the internal structure of RecA in the active filament are not markedly altered when the bound DNA changes from single- to double-stranded. The implications of the structural similarities as well as the significance of some conformational variations observed for a few amino acid residues that may be involved in interactions with DNA are discussed.

DNA, Bacterial↗
PubMed2003

An investigation of cysteine mutants on the cytoplasmic loop X/XI in the melibiose transporter of Escherichia coli by using thiol reagents: implication of structural conservation of charged residues.

The melibiose transporter (Mel B) of Escherichia coli is a cation-coupled (H(+), Li(+), and Na(+)) membrane protein (MW 50 kDa) consisting of 12 transmembrane helices that are connected by periplasmic and cytoplasmic loops, with both the C- and N-ends located on the cytoplasmic side of the membrane. Previous investigations on the largest cytoplasmic loop X/XI indicated that it is a functional re-entrant loop. In this communication, the cysteine mutants on loop X/XI were studied with charged thiol reagents MTSES, MTSET, and IAA for both the inhibition patterns and charge replacement/function rescue of inactive mutants in which the original charged residues were replaced by neutral cysteines. Strong inhibitions were observed in T373C and V376C by both MTSES and MTSET, consistent with previous results of PCMBS inhibition. The thiol reagents failed to recover the activities of inactive mutants D351C, D354C, and R363C and to inhibit active mutants E357C, K359C, and E365C to any significant extent, suggesting a structural conservation at D351, D354, and R363 and tolerance of structural variations at E357, K359, and E365. The results are consistent with previous observation of structural conservation of functionally charged residues in the transmembrane domains and extend to a loop the contention that in the melibiose transporter functionally important charged residues are structurally conserved.

4-Chloromercuribenzenesulfonate↗
PubMed2005

Chemoenzymatic synthesis of cryptophycin/arenastatin natural products.

Microbially derived modular polyketide synthase and nonribosomal peptide synthetase biosynthetic pathways are a rich source of novel natural products. Development of these systems for the engineered biosynthesis of diverse secondary metabolites continues to progress as a robust source of chemical diversity. Recent efforts that employ individual enzymes and catalytic domains for the production or modification of small molecules have met with growing success. In this study, the thioesterase domain from the cryptophycin biosynthetic pathway was isolated and its function evaluated with a series of linear chain elongation intermediates in developing a novel chemoenzymatic synthesis of the cryptophycin/arenastatin class of antitumor agents. The results show the high efficiency of the thioesterase in generating the 16-membered depsipeptide ring of this important natural product system. Moreover, analysis of selected substrates revealed considerable tolerance for structural variation within the seco-cryptophycin unit C beta-alanine residue, but strict structural requirements at the phenyl group position of the unit A delta-hydroxy octadienoate chain elongation intermediates.

Amino Acid Sequence↗
PubMed2002

Identification and sequencing of HLA-B*0714 and B*2718 alleles and novel exon 1 sequences of B*0709 and B*2714 alleles in potential bone marrow donors.

Sequence specific oligonucleotide probe hybridization and sequence specific primer PCR typing of volunteer bone marrow donors suggested the presence of variants of known HLA-B alleles in two individuals. PCR products encompassing HLA-B locus exons 1, 2, and 3 were prepared, subcloned and sequenced. A Hispanic individual had a novel B*07 allele (B*0714) and a Chinese individual had a novel B*27 allele (B*2718). In two other individuals, a previously unknown sequence of exon 1 was determined for HLA-B*0709 (African American) and B*2714 (Native American). These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations. We discuss the structural variation in the protein sequence for these HLA-B alleles and its potential functional effects.

Asian People↗
PubMed2004

The mother-infant relationship in single, cohabiting, and married families: a case for marriage?

Single-mother, cohabiting 2-parent, and married 2-parent families with infants were compared on maternal and infant behavior, Home Observation for Measurement of the Environment (HOME) scores, and infant's security of attachment. Married mothers and their infants demonstrated more positive behavior and received higher HOME scores when the infant was 6 and 15 months old than did their cohabiting and single counterparts. Married families were also better off than single and cohabiting families on several demographic, parent personality, financial, and social context measures. Single and cohabiting families were similar across most measures. Selection variables (maternal age, ethnic group, and education) explained much, but not all, of the family structure differences in the mother-infant relationship and the HOME. Maternal psychological adjustment, attitudes about child rearing, income, and social support explained little of the family structure variation, suggesting that characteristics that preceded marriage and conception were important determinants of family structure differences.

Adolescent↗
PubMed1997

Sialic acids as ligands in recognition phenomena.

The sialic acids are acidic monosaccharides typically found at the outermost ends of the sugar chains of animal glycoconjugates. They potentially can inhibit intermolecular and intercellular interactions by virtue of their negative charge. However, they can also act as critical components of ligands recognized by a variety of proteins of animal, plant, and microbial origin (sialic acid binding lectins). Recognition can be affected by specific structural variations and modifications of sialic acids, their linkage to the underlying sugar chain, the structure of these chains, and the nature of the glycoconjugate to which they are attached. Presented here is a summary of the various proteins that can recognize and bind to this family of monosaccharides, comparing and contrasting the structural requirements and mechanisms involved in binding. Particular attention is focused on the recently evolving information about sialic acid recognition by certain C-type lectins (the selectins), I-type lectins (e.g., CD22 and sialoadhesin), and a complement regulatory protein (the H protein). The last two instances are examples of the importance of the side chain of sialic acids and the effects of natural substitutions (e.g., 9-O-acetylation) of this part of the molecule.

Carbohydrate Sequence↗
PubMed2006

Efficient molecular docking of NMR structures: application to HIV-1 protease.

Docking ligands into an ensemble of NMR conformers is essential to structure-based drug discovery if only NMR structures are available for the target. However, sequentially docking ligands into each NMR conformer through standard single-receptor-structure docking, referred to as sequential docking, is computationally expensive for large-scale database screening because of the large number of NMR conformers involved. Recently, we developed an efficient ensemble docking algorithm to consider protein structural variations in ligand binding. The algorithm simultaneously docks ligands into an ensemble of protein structures and achieves comparable performance to sequential docking without significant increase in computational time over single-structure docking. Here, we applied this algorithm to docking with NMR structures. The HIV-1 protease was used for validation in terms of docking accuracy and virtual screening. Ensemble docking of the NMR structures identified 91% of the known inhibitors under the criterion of RMSD < 2.0 A for the best-scored conformation, higher than the average success rate of single docking of individual crystal structures (66%). In the virtual screening test, on average, ensemble docking of the NMR structures obtained higher enrichments than single-structure docking of the crystal structures. In contrast, docking of either the NMR minimized average structure or a single NMR conformer performed less satisfactorily on both binding mode prediction and virtual screening, indicating that a single NMR structure may not be suitable for docking calculations. The success of ensemble docking of the NMR structures suggests an efficient alternative method for standard single docking of crystal structures and for considering protein flexibility.

Algorithms↗
PubMed1989

Governing boards and profound organizational change in hospitals.

Over the past decade the importance of governing boards as policy-making setting and oversight units within organizations has increased dramatically. Although this is true for both corporate- and private-sector organizations (Bacon and Brown 1977; Gelman 1988), it is particularly relevant to the health sector. Hospital governing boards, long considered inconsequential in hospital management, have recently become subject to closer scrutiny. The role of governing boards in decisions affecting hospital strategy and hospital performance is once again a topic of some interest in boardrooms and hospital trade journals. Impressive evidence of the renewed interest in governance is provided by the funding of an instructional consortium by the S.K. Kellogg Foundation to help strengthen trusteeship and governing board decision making, and to improve education for health services managers in the area of governance. Members of the consortium include the Hospital Research and Educational Trust, the American Hospital Association, the American College of Healthcare Executives, and the Association for University Programs in Health Administration. Among the activities being undertaken by this consortium is the development of a self-assessment tool/methodology for boards, a bibliography and reference guide on effective governance for practicing trustees, research workshops for faculty in health administration programs, and a teaching guide on governance and trustee leadership. Despite this interest, the question with which we began this article persists. Do governing boards make a difference? In the course of our review of previous work on governance we found that, more often than not, that question has been transformed into: how do boards influence hospital performance? And very often that question has been further narrowed into: which board structure leads to better hospital performance? We have argued for a respecification of the initial question. Rather than pursuing a definition of the maximally performing governing board, we should perhaps shift our focus back to a fuller understanding of board structure and function, and its influence on hospital change. The model developed here combines four essential, and very basic, questions: 1. What are the basic dimensions that underlie structural variation in different types of governing boards? 2. How do these board types influence structural change in hospitals? 3. How is the effect of board influence on change itself likely to change over time as a function of the hospital's general pattern of growth, decline, stability, or instability?(ABSTRACT TRUNCATED AT 400 WORDS)

Decision Making, Organizational↗