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PubMed1991

The DNA sequence at echinomycin binding sites determines the structural changes induced by drug binding: NMR studies of echinomycin binding to [d(ACGTACGT)]2 and [d(TCGATCGA)]2.

The complexes formed between the cyclic octadepsipeptide antibiotic echinomycin and the two DNA octamers [d(ACGTACGT)]2 and [d(TCGATCGA)]2 have been investigated by using one- and two-dimensional proton NMR spectroscopy techniques. The results obtained for the two complexes are compared to each other, to the crystal structures of related DNA-echinomycin complexes, and to enzymatic and chemical footprinting results. In the saturated complexes, two echinomycin molecules bind to each octamer by bisintercalation of the quinoxaline moieties on either side of each CpG step. Binding of echinomycin to the octamer [d(ACGTACGT)]2 is cooperative so that only the two-drug complex is observed at lower drug-DNA ratios, but binding to [d(TCGATCGA)]2 is not cooperative. At low temperatures, both the internal and terminal A.T base pairs adjacent to the binding site in the [d(ACGTACGT)]2-2 echinomycin complex are Hoogsteen base paired (Gilbert et al., 1989) as observed in related crystal structures. However, as the temperature is raised, the internal A.T Hoogsteen base pairs are destabilized and are observed to be exchanging between the Hoogsteen base-paired and an open (or Watson-Crick base-paired) state. In contrast, in the [d(TCGATCGA)]2-2 echinomycin complex, no A.T Hoogsteen base pairs are observed, the internal A.T base pairs appear to be stabilized by drug binding, and the structure of the complex does not change significantly from 0 to 45 degrees C. Thus, the structure and stability of the DNA in echinomycin-DNA complexes depends on the sequence at and adjacent to the binding site. While we conclude that no single structural change in the DNA can explain all of the footprinting results, unwinding of the DNA helix in the drug-DNA complexes appears to be an important factor while Hoogsteen base pair formation does not.

Base Sequence↗

PubMed1997

Analysis of pH-induced structural changes of the isolated extrinsic 33 kilodalton protein of photosystem II.

Structural properties of the isolated extrinsic regulatory 33 kDa protein of the water-oxidizing complex were analyzed at different pH values. It was found that (a) titrations of the buffer capacity reveal a characteristic hysteresis effect that is unique for the 33 kDa subunit and is not observed for the other extrinsic proteins, (b) changes of the emission from the fluorescence probe 1,8-ANS are indicative of an increased accessibility of the hydrophobic core of the 33 kDa protein to the dye at lower pH, (c) the near-UV circular dichroism spectrum of the polypeptide is altered owing to a pH decrease from 6.8 to 3.8 and becomes drastically changed at pH 2.8, and (d) the content of secondary structure elements remains virtually constant in the range 3.8 < pH < 6.8, with the following values gathered from far-UV CD spectra: approximately 8% alpha-helix, approximately 33% beta-strand, approximately 15% turns, and approximately 44% random coil. Further acidification down to pH 2.8 gives rise to a decreased alpha-helix and increased beta-strand and random coil content. A theoretical model [Ptitsyn, O., & Finkelstein, A. (1983) Biopolymers 2, 15-22] was used to predict the probability and location of secondary structure elements within the protein sequence. On the basis of these calculations, an extended hydrophobic beta-sheet domain could exist in the center of the protein and an alpha-helix in the C-terminal region. From these data, the 33 kDa protein is inferred to change its tertiary structure in vitro upon acidification of the aqueous environment. Possible implications of these features are discussed.

Anilino Naphthalenesulfonates↗

PubMed2001

Early stages of LDL oxidation: apolipoprotein B structural changes monitored by infrared spectroscopy.

Changes in the conformation of apoliprotein B-100 in the early stages of copper-mediated low density lipoprotein oxidation have been monitored by infrared spectroscopy. During the lag phase no variation in structure is observed, indicating that copper binding to the protein does not significantly affect its structure. In the propagation phase, while hydroperoxides are formed but the protein is not modified, no changes in secondary structure are observed, but the thermal profile of the band corresponding to alpha-helix is displaced in frequency, indicating changes in tertiary structure associated with this conformation but not with beta-sheet components. When aldehyde formation starts, a decrease of approximately 3% in the area of bands corresponding to alpha-helix and beta-sheet is produced, concomitantly with an increase in beta-turns and unordered structure. The two bands corresponding to beta-turns vary as well under these conditions, indicating changes in these structures. Also at this stage the thermal profile shows variations in frequency for the bands corresponding to both alpha-helix and beta-sheet. The results are consistent with the hypothesis that as soon as the polyunsaturated fatty acids from the particle core are modified, this change is reflected at the surface, in the alpha-helical components contacting the monolayer.

Apolipoproteins B↗

PubMed1986

Structural changes in retinol binding protein induced by retinol removal. A molecular dynamics study.

Relationships between structure and function for retinol binding protein (RBP) are elucidated with help of a 2.0 A resolution X-ray structure of the holo-protein and an average molecular dynamics (MD) structure of the apo-form. Comparisons between MD simulations of both the apo- and holo-forms with the X-ray holo-structure show conformational changes in apo-RBP that may be functionally significant. The average three dimensional structure obtained for apo-RBP is compared to the related protein apo-beta-lactoglobulin. Available biochemical information is consistent with structure/function relationships derived here.

Humans↗

PubMed2006

Roles for Arg426 and Trp111 in the modulation of NADH oxidase activity of the catalase-peroxidase KatG from Burkholderia pseudomallei inferred from pH-induced structural changes.

Crystals of Burkholderia pseudomallei KatG retain their ability to diffract X-rays at high resolution after adjustment of the pH from 5.6 to 4.5, 6.5, 7.5, and 8.5, providing a unique view of the effect of pH on protein structure. One significant pH-sensitive change lies in the appearance of a perhydroxy group attached to the indole nitrogen of the active site Trp111 above pH 7, similar to a modification originally observed in the Ser324Thr variant of the enzyme at pH 5.6. The modification forms rapidly from molecular oxygen in the buffer with 100% occupancy after one minute of soaking of the crystal at room temperature and pH 8.5. The low temperature (4 K) ferric EPR spectra of the resting enzyme, being very sensitive to changes in the heme iron microenvironment, confirm the presence of the modification above pH 7 in native enzyme and variants lacking Arg426 or Met264 and its absence in variants lacking Trp111 or Tyr238. The indole-perhydroxy group is very likely the reactive intermediate of molecular oxygen in the NADH oxidase reaction, and Arg426 is required for its reduction. The second significant pH-sensitive change involves the buried side chain of Arg426 that changes from one predominant conformation at low pH to a second at high pH. The pH profiles of the peroxidase, catalase, and NADH oxidase reactions can be correlated with the distribution of Arg426 conformations. Other pH-induced structural changes include a number of surface-situated side chains, but there is only one change involving a displacement of main chain atoms triggered by the protonation of His53 in a deep pocket in the vicinity of the molecular 2-fold axis.

Arginine↗

PubMed2000

Energetics of the induced structural change in a Ca2+ regulatory protein: Ca2+ and troponin I peptide binding to the E41A mutant of the N-domain of skeletal troponin C.

Structural studies have shown that the regulatory domains of skeletal and cardiac troponin C (sNTnC and cNTnC) undergo different conformational changes upon Ca(2+) binding; sNTnC "opens" with a large exposure of the hydrophobic surface, while cNTnC retains a "closed" conformation similar to that in the apo state. This is mainly due to the fact that there is a defunct Ca(2+)-binding site I in cNTnC. Despite the striking difference, the two proteins bind their respective troponin I (TnI) regions (sTnI(115-131) and cTnI(147-163), respectively) in a similar open fashion. Thus, there must exist a delicate energetic balance between Ca(2+) and TnI binding and the accompanying conformational changes in TnC for each system. To understand the coupling between Ca(2+) and TnI binding and the concomitant structural changes, we have previously engineered an E41A mutant of sNTnC and demonstrated that this mutation drastically reduced the Ca(2+)-binding affinity of site I in sNTnC, and as a result, E41A-sNTnC remains closed in the Ca(2+)-bound state. In the present work, we investigated the interaction of E41A-sNTnC with the sTnI(115-131) peptide and found that the peptide binds to the Ca(2+)-saturated E41A-sNTnC with a 1:1 stoichiometry and a dissociation constant of 300 +/- 100 microM. The peptide-induced chemical shift changes resemble those of Ca(2+) binding to sNTnC, suggesting that sTnI(115-131) induces the "opening" of E41A-sNTnC. In addition, the binding of sTnI(115-131) appears to be accompanied by a conformational change in site I of E41A-sNTnC so that the damaged regulatory site can bind Ca(2+) more tightly. Without Ca(2+), sTnI(115-131) only interacts with E41A-sNTnC nonspecifically. When Ca(2+) is titrated into E41A-sNTnC in the presence of sTnI(115-131), the Ca(2+)-binding affinity of site I was enhanced by approximately 5-fold as compared to when sTnI(115-131) was not present. These observations suggest that the binding of Ca(2+) and TnI is intimately coupled to each other. Together with our previous studies on Ca(2+) and TnI peptide binding to sNTnC and cNTnC, these results allow us to dissect the mechanism and energetics of coupling of ligand binding and structural opening intricately involved in the regulation of skeletal and cardiac muscle contraction.

Alanine↗

PubMed1997

Structural change and receptor binding in a chemokine mutant with a rearranged disulfide: X-ray structure of E38C/C50AIL-8 at 2 A resolution.

The characteristic CXC chemokine disulfide core of interleukin-8 (IL-8) has been rearranged in a variant replacing the 9-50 disulfide with a 9-38 disulfide. The new variant has been characterized by its binding affinity to IL-8 receptors A and B and the erythrocyte receptor DARC. This variant binds the three receptors with affinities between 500- and 2,500-fold lower than wild-type IL-8. Binding affinity results are also reported for the variant with alanine substituted for both cysteines 9 and 50. The Glu38-->Cys/Cys50-->Ala IL-8 crystallizes in space group P2(1)2(1)2(1) with cell parameters a = 46.4, b = 49.2, and c = 69.5 A, and has been refined to an R-value of 19.4% for data from 10 to 2 A resolution. Analysis of the structure confirms the new disulfide arrangement and suggests that changes at Ile10 may be the principal cause of the lowered affinities.

Antigens, CD↗

PubMed1986

[Structural changes in popliteal lymph nodes in the graft vs. host reaction to H-Y antigen in male C57BL/6-strain mice].

Regional popliteal lymph nodes in intact, control and experimental (I, II, III groups, respectively) have been studied by means of the morphometric method in male C57Bl/6 line mice at the pick of the reaction produced by injection of spleen cells and mesenteric lymph nodes obtained from syngenic females and repeatedly immunized to H-Y antigen (10 animals in each group). Injection of the cell suspensions from the immunized and intact females of the C57Bl/6 mice result nearly in two-fold increasing mass of the regional popliteal node at the expense of enlarged size of all its zones. Changes in cytoarchitectonics of the node structural components result from redistribution of certain cellular elements. The essential changes in the cell composition of the lymph nodes in the II and III male groups are accompanied with an increasing part of the stromal reticular cells. Simultaneously, content of small lymphocytes decreases significantly. In the III group of mice there is a sharp increase in the content of young forms of the lymphoid line cells in all structural components of the node, as well as in eosinophilic granulocytes in medullary cords. In the dark cortical zone of the nodes (III group) there occur tissue basophils (mast cells), that, together with increasing number of acidophilic granulocytes and appearance of neutrophilic cells, demonstrates that there is an inflammatory reaction in the organ studied as a response to the lymphocytic suspension injected. In the experimental group of the animals a complete disappearance of plasma cells is noted in the node cortex, but some increase of their part takes place in the medullary cords.

Animals↗

PubMed1976

Suppressor-induced structural changes in a missense L-ribulokinase of Escherichia coli.

A suppressor mutation specific for a missense codon in the L-ribulokinase structural gene of the L-arabinose operon of Escherichia coli B/r enhanced L-arabinose utilization by the strain containing the missense codon. Electrophoretic comparisons of the wild-type, missense, and suppressed missense L-ribulokinases indicated that the suppressor changed the structure of the missense kinase, thereby increasing its catalytic activity. Hyperinducibility imposed on an operator-distal gene by the missense codon was not affected by the suppressor mutation.

Arabinose↗

PubMedDate not supplied

The changing structure of the pharmaceutical industry.

Rising research and development (R&D) expenditures by pharmaceutical companies are, in part, a consequence of changing industry structure, particularly the rise of the biotechnology sector. The creation of a market for biomedical science and increased vertical competition within the industry are likely to spur innovation and raise productivity, but they also could induce socially wasteful spending and weaken academic science. With innovation increasingly dependent on financially vulnerable firms and complex contractual arrangements, R&D investment might be becoming more sensitive to price controls or other cost containment measures.

Drug Industry↗

PubMed1998

On the structural changes of native human alpha2-macroglobulin upon proteinase entrapment. Three-dimensional structure of the half-transformed molecule.

The reconstructions of an intermediate form of human alpha2-macroglobulin (half-transformed alpha2M) in which two of its four bait regions and thiol ester sites were cleaved by chymotrypsin bound to Sepharose were obtained by three-dimensional electron microscopy from stain and frozen-hydrated specimens. The structures show excellent agreement and reveal a structure with approximate dimensions of 195 (length) x 135 (width) and 130 A (depth) with an internal funnel-shaped cavity. The structure shows that a chisel-shaped body is connected to a broad base at the opposing end by four stands. Four approximately 45 A diameter large openings in the body of the structure result in a central cavity that is more accessible to the proteinase than those associated with the native or fully transformed structures. The dissimilarity in the shapes between the two ends of alpha2M half-transformed and the similarity between its chisel-shaped body and that of native alpha2M indicate that the chymotrypsin has cleaved both bait regions in the bottom-half of the structure. Consequently, its functional division lies on the minor axis. The structural organization is in accord with biochemical studies, which show that the half-transformed alpha2M migrates on native polyacrylamide gels at a rate intermediate to the native and fully transformed alpha2M and is capable of trapping 1 mol of proteinase. Even though its upper portion is similar to the native molecule, significant differences in their shapes are apparent and these differences may be related to its slower reaction with a proteinase than the native structure. These structural comparisons further support the view that the transformation of alpha2M involves an untwisting of its strands with an opening of the cavity for entrance of the proteinase and a retwisting of the strands around the proteinase resulting in its encapsulation.

Binding Sites↗

PubMed1987

Fine-structural changes of synapses in the superior cervical ganglion of adult rats after long-term administration of GABA. A morphometric analysis.

The superior cervical ganglion (SCG) of adult rats was exposed to gamma-aminobutyric acid (GABA) by means of long-term microapplication. Serial sections were cut from GABA-treated and control ganglia, and subsequently the fine structure of individual synapses was investigated. The quantitative analysis of structural parameters of studied synapses showed that significant changes consisting of (1) a reduction in size of presynaptic axon terminals, (2) a decrease in the number of synaptic vesicles, and (3) a diminution in the extent of the postsynaptic membrane thickening at the dendritic side developed as an effect of GABA-treatment. These results provide morphological evidence that long-term application of GABA to the SCG exerts a combination of effects on both presynaptic and postsynaptic elements. It is suggested that the structural changes observed in the fine structure of individual synapses within the SCG may play an integral role in the development of the synaptogenetic action of GABA.

Animals↗

PubMed1993

Asp96 deprotonation and transmembrane alpha-helical structural changes in bacteriorhodopsin.

The M-->N transition in the photocycle of bacteriorhodopsin involves the transfer of a proton from Asp96 to the retinylidene Schiff base, possibly through a network of hydrogen-bonded amino acid residues and water molecules (Rothschild, K. J., He, Y. W., Sonar, S., Marti, T., and Khorana, H. G. (1992) J. Biol. Chem. 267, 1615-1622). A conformational change of the protein backbone is also observed during this transition. In this work, we have investigated the effects of replacing the residue Thr46, which might be part of this chain, with an aspartic acid. Both Fourier transform infrared and resonance Raman spectroscopy show that the chromophore structure of this mutant (T46D) is normal. However, N formation is accelerated and N decay is significantly slowed compared to wild-type bacteriorhodopsin. This effect causes the N intermediate to accumulate under steady-state illumination thereby facilitating spectroscopic studies under normal pH conditions. Fourier transform infrared difference spectroscopy reveals that like native bacteriorhodopsin, N formation in T46D involves deprotonation of Asp96, reprotonation of the Schiff base, and a change in the backbone secondary structure. However, in contrast to bacteriorhodopsin, bands assigned to the C = O stretch mode of the carboxylic acid group of Asp96 are upshifted by 10 cm-1 reflecting a change in the Asp96 environment and a drop in its effective pKa throughout the photocycle. This change in the pKa can directly account for changes in the photocycle kinetics and indicates that Asp96 deprotonation/protonation are the rate limiting steps in the formation and decay of the N intermediate. By studying the effects of H/D exchange, evidence is found that the backbone structural changes involve transmembrane alpha-helices. It is proposed that these structural changes serve to modulate the local environment and protonation state of Asp96 during the photocycle and are also essential for formation of the proton conducting hydrogen bonded network which functions during Schiff base reprotonation.

Aspartic Acid↗

PubMed1995

Structural changes in the oviductal wall during passage of unfertilized cumulus-oocyte complexes in mice.

BACKGROUND: Little information is available on the structural relationship of cumulus-oocyte complexes and the oviductal wall during the transport of cumulus-oocyte complexes. METHODS: To this end, morphological changes of the oviductal wall during the passage of unfertilized cumulus-oocyte complexes were examined chronologically in ICR mice 25-27 days of age injected with PMSG and hCG. Mice were sacrificed at 12, 14, 16, 18, and 24 hr after the injection of hCG to remove oviducts, and the height of mucosal folds, muscle layers, and epithelial cells was measured in the serial sections stained with hematoxylineosin or colloidal iron. RESULTS: The height of the mucosal fold and muscle layer where cumulus-oocyte complexes were located was less than that of the adjacent portions. At 12-18 hr of hCG injection (approximately 2-8 hr after ovulation), the ova with surrounding cumulus cells lie free in a wide lumen, and the muscular tissue consists of only 2 or 3 layers of cells, arranged mostly longitudinally. However, a neighboring portion without cumulus-oocyte complexes, where the folds meet in the middle, appreciably restricts the free space in the lumen. After 24 hr of hCG administration, structural changes in the oviductal wall, where cumulus-oocyte complexes were located, were no longer apparent. The number of cumulus cells surrounding the oocyte decreased during the passage through the oviduct. At 12-18 hr after hCG injection, approximately 140 cells were identified in the largest cross section of a cumulus-oocyte complex, but after 24 hr of hCG administration (approximately 14 hr after ovulation), an oocyte was surrounded with only approximately 25 cells. CONCLUSIONS: These results indicate that oocyte-cumulus cell complexes influence the structure of the oviductal wall during the passage in the oviduct.

Animals↗

PubMed1996

Upper airway and soft tissue structural changes induced by CPAP in normal subjects.

Nasal continuous positive airway pressure (CPAP) is the treatment of choice for adults with obstructive sleep apnea. CPAP is known to increase upper airway size; however, the direct effects of CPAP on soft tissue structures surrounding the upper airway are less well understood. Magnetic resonance imaging was used to study the effect of incremental levels (0, 5, 10, and 15 cm H2O) of CPAP on the upper airway and surrounding soft tissue structures in 10 normal subjects. Progressive increases in CPAP resulted in the following major findings: (1) airway volume and airway area (measured at several different locations [midregion, minimal, maximal]) within the retropalatal and retroglossal regions increased; (2) lateral airway dimensional changes were greater than anterior-posterior changes; (3) lateral upper airway soft tissue structural changes were significantly greater than anterior-posterior changes; (4) lateral pharyngeal wall thickness decreased and the distance between the lateral parapharyngeal fat pads increased. An inverse relationship was demonstrated between CPAP level and pharyngeal wall thickness; (5) minimal changes were noted in the soft palate and tongue. These data suggest that the lateral pharyngeal walls are more "compliant" than the soft palate and tongue. This investigation provides further evidence that the lateral pharyngeal walls play an important role in mediating upper airway caliber.

Adult↗

PubMed1995

Structural changes in the oviductal wall during the passage of unfertilized cumulus-oocyte complexes in mice.

BACKGROUND: Little information is available on the structural relationship of cumulus-oocyte complexes and the oviductal wall during the transport of cumulus-oocyte complexes. Then, morphological changes of the oviductal wall during the passage of unfertilized cumulus-oocyte complexes was examined chronologically in ICR mice 25-27 days of age injected with PMSG and hCG. METHODS: Mice were sacrificed at 12, 14, 16, 18, and 24 hr after the injection of hCG to remove oviducts, and the height of mucosal folds, muscle layers, and epithelial cells were measured in the serial sections stained with hematoxylin-eosin or colloidal iron. RESULTS: The height of the mucosal fold and muscle layer where cumulus-oocyte complexes were located was less than that of the adjacent portions. At 12-18 hr of hCG injection (about 2-8 hr after ovulation), the ova with surrounding cumulus cells lie free in a wide lumen, and the muscular tissue consists of only 2 or 3 layers of cells, arranged mostly longitudinally. However, a neighboring portion without cumulus-oocyte complexes, where the folds meet in the middle, appreciably restricts the free space in the lumen. After 24 hr of hCG administration, structural changes in the oviductal wall, where cumulus-oocyte complexes were located, were no longer apparent. The number of cumulus cells surrounding the oocyte decreased during the passage through the oviduct. At 12-18 hr after hCG injection, about 140 cells were identified in the largest cross section of a cumulus-oocyte complex, but, after 24 hr of hCG administration (about 14 hr after ovulation), an oocyte was surrounded with only about 25 cells. CONCLUSIONS: These results indicate that oocyte-cumulus cell complexes influence the structure of the oviductal wall during the passage in the oviduct.

Animals↗

PubMedDate not supplied

[Structural changes in the brain in HIV infection complicated by drug addiction].

Comparative analysis of brain alterations in drug addicts who were HIV-seropositive and died of sepsis and HIV-seronegative addicts showed similarity of these changes which manifested with ganglion cell rarefaction and losses, changed neuron content of main structural-functional types; massive satellitosis and neuronophagia, massive glycosis and leucodystrophy. These changes were diffuse in seropositive patients and rather focal in seronegative patients. The authors, on the basis of these findings, suggest a wider spread of HIV infection in drug addicts; they express doubts in the secondary nature of HIV-encephalopathy and believe that drug addiction should be considered as factor promoting HIV-infection development.

Brain↗

PubMed1994

Dose-effect relations for local functional and structural changes of the lung after irradiation for malignant lymphoma.

PURPOSE: To estimate the dose-effect relations for local functional (ventilation and perfusion) and structural (density) changes of the lung, 3-4 months after irradiation. METHODS: Twenty-five patients with malignant lymphoma were irradiated with a (modified) mantle field to an average dose of 38 Gy, given in 21 fractions. Single photon emission computed tomography (SPECT) ventilation (V) and perfusion (Q) scans, and CT scans were performed before and 3-4 months after radiation treatment. The three-dimensional dose distribution was calculated using the CT data. After correlation of SPECT and CT data sets, the average post-treatment value of V, Q and lung density per voxel was calculated relative to the pre-treatment value, per dose interval of 4 Gy. Subsequently, the dose-effect relations in each patient were normalized to the average value per voxel in the dose interval of 0-12 Gy. In addition, in each dose interval of 4 Gy the fraction of patients with changes larger than 20% was calculated for all three parameters. The dose-effect relations for perfusion and ventilation normalized to the low-dose regions, and the dose-incidence curves for the fraction of patients with changes larger than 20% were fitted for all three parameters, using a logistic model. RESULTS: Marked changes in the distribution of V and Q were found after irradiation. Prior to normalization to the low-dose regions, a change in V and Q was found in most patients in the dose interval of 0-12 Gy, varying from an increase of 37% to a decrease of 10%, which was followed by a decreasing trend at higher doses. The increase in the low-dose regions indicated a redistribution phenomenon, the magnitude of which was dependent of the irradiated volume. The logistic fit of the dose-effect relations for Q and V, normalized to the low-dose regions, resulted in values for D50 of 51 Gy and 54 Gy (given in 21 fractions on average), respectively, and for the steepness parameter k of 4.2 and 4.0, respectively. The logistic fit for the dose-incidence curves for Q, V and lung density resulted in values for D50 and k of 38 Gy, 37 Gy, 44 Gy and 10.3, 7.8 and 9.4, respectively. CONCLUSIONS: With the combined use of SPECT and CT scans, we have obtained dose-effect relations for local functional and structural damage in the lung, 3-4 months after irradiation.

Adolescent↗