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At least 469 records · Page 26Linked to original sources
PubMed2003

Different dissolution media lead to different crystal structures of talinolol with impact on its dissolution and solubility.

During the performance of dissolution tests with immediate and controlled-release talinolol tablets it was detected that the type of the buffer used as dissolution medium had a strong influence on the solubility and the dissolution behavior of the drug. It was proven that talinolol appeared in different crystal structures with strongly differing solubilities when pure water, acetate, or phosphate buffers were employed as dissolution media. The resulting crystal structures were characterized by means of light microscopy, differential scanning calorimetry, and X-ray powder diffraction. All methods were adjuvant to detect changes in talinolol crystal structures. The different solubility and dissolution properties of the talinolol salts or modifications may be viewed as a source for its incomplete and variable bioavailability. Furthermore, the food effect, described in the literature, that leads to a decrease in talinolol absorption, could be due to changes in the composition of gastrointestinal fluids leading to different talinolol crystal structures. Furthermore, it was detected that the addition of sodium chloride increases talinolol solubility and accelerates its dissolution from controlled-release tablets at concentrations between 0% and 1.25%, while an addition of sodium dodecylsulfate (SDS) as surfactant only had a solubility-improving effect at concentrations > 0.75%. At lower concentrations SDS decreased the solubility of talinolol and notably decelerated its release from controlled-release tablets.

Adrenergic beta-Antagonists↗
PubMed1996

Crystal structure, receptor binding, and gene regulation of 2- and 4-nitroestradiols.

Crystal structures of 2-nitroestradiol and 4-nitroestradiol showed two different molecular conformations for each compound. The crystal structure of 4-nitroestradiol, as well as that of 4-nitroestrone-3-methyl ether, displayed a nitro group in which the oxygens were perpendicular to the aromatic ring and were this nonconjugating. On the other hand, the nitro-oxygens in 2-nitroestradiol were periplanar, with the aromatic ring permitting conjugating. This latter structure bound to estrogen receptor with 1/1000th the affinity of estradiol and was inefficient in gene stimulation. 4-Nitroestradiol possessed a relative binding affinity 40-fold greater than that of the 2-nitro derivative and actively induced responsive genes at a concentration of 10(-8) M. Whereas binding affinity can be explained primarily by polar groups and skeletal structure, gene induction may be linked to electronic induction in ring A that causes a requisite electronegative isopotential around the molecule. This electronegative characteristic also produces conformational changes in the alicyclic backbone of the estrogen, specially ring B, which could interfere with the molecular fit of the nitroestradiols with estrogen receptor.

Cell Line↗
PubMed1991

High-resolution solution structure of reduced French bean plastocyanin and comparison with the crystal structure of poplar plastocyanin.

The three-dimensional solution structure of reduced (CuI) plastocyanin from French bean leaves has been determined by distance geometry and restrained molecular dynamics methods using constraints obtained from 1H n.m.r. (nuclear magnetic resonance) spectroscopy. A total of 1244 experimental constraints were used, including 1120 distance constraints, 103 dihedral angle constraints and 21 hydrogen bond constraints. Stereospecific assignments were made for 26 methylene groups and the methyls of 11 valines. Additional constraints on copper co-ordination were included in the restrained dynamics calculations. The structures are well defined with average atomic root-mean-square deviations from the mean of 0.45 A for all backbone heavy atoms and 1.08 A for side-chain heavy atoms. French bean plastocyanin adopts a beta-sandwich structure in solution that is similar to the X-ray structure of reduced poplar plastocyanin; the average atomic root-mean-square difference between 16 n.m.r. structures and the X-ray structure is 0.76 A for all backbone heavy atoms. The conformations of the side-chains that constitute the hydrophobic core of French bean plastocyanin are very well defined. Of 47 conserved residues that populate a single chi 1 angle in solution, 43 have the same rotamer in the X-ray structure. Many surface side-chains adopt highly preferred conformations in solution, although the 3J alpha beta coupling constants often indicate some degree of conformational averaging. Some surface side-chains are disordered in both the solution and crystal structures of plastocyanin. There is a striking correlation between measures of side-chain disorder in solution and side-chain temperature factors in the X-ray structure. Side-chains that form a distinctive acidic surface region, believed to be important in binding other electron transfer proteins, appear to be disordered. Fifty backbone amide protons form hydrogen bonds to carbonyls in more than 60% of the n.m.r. structures; 45 of these amide protons exchange slowly with solvent deuterons. Ten hydrogen bonds are formed between side-chain and backbone atoms, eight of which are correlated with decreased proton exchange. Of the 60 hydrogen bonds formed in French bean plastocyanin, 56 occur in the X-ray structure of the poplar protein; two of the missing hydrogen bonds are absent as a result of mutations. It appears that molecular dynamics refinement of highly constrained n.m.r. structures allows accurate prediction of the pattern of hydrogen bonding.

Amino Acid Sequence↗
PubMed1989

Crystal structure of a cAMP-independent form of catabolite gene activator protein with adenosine substituted in one of two cAMP-binding sites.

Catabolite gene activator protein (CAP) in the presence of cAMP stimulates transcription from several operons in Escherichia coli. A cAMP-independent variant, in which Ala-144 is replaced by Thr (CAP91), is activated by analogues of cAMP, such as adenosine, which do not activate the wild-type CAP. In order to test the effect of adenosine on the structure, a crystal of CAP91 grown as a complex with cAMP was soaked in a solution of 10 mM adenosine, and X-ray diffraction data were measured to 3.5-A resolution. The difference Fourier map calculated with phases from the CAP91 structure showed significant negative density at the position of the phosphate of cAMP bound in one subunit of the CAP91 dimer. Adenosine was preferentially substituted for cAMP in the subunit in the "closed" conformation, while the cAMP-binding site of the "open" subunit was apparently still occupied by cAMP. The structure was refined by restrained least-squares methods to an R factor of 20.2%. Adenosine is not bound in exactly the same position as cAMP; instead, the 5'-OH of adenosine is in a new position that allows formation of two hydrogen bonds with Ser-83, replacing two of the three interactions of the phosphate of cAMP with Arg-82 and Ser-83.

Adenosine↗
PubMed1997

A DNA decamer with a sticky end: the crystal structure of d-CGACGATCGT.

The crystal structure of d-CGACGATCGT has been determined to a resolution of 2.6 A. The molecule was synthesized by standard phosphoramidite procedures, and purified by anion-exchange HPLC. Crystals are monolclinic, space group P2(1), with unit cell dimensions, a = 26.45 A, b = 34.66 A, c = 32.17 A, beta = 113.45 degrees and Z = 4, containing a B-DNA double helix in each crystallographic asymmetric unit. The structure was solved using molecular replacement, aided by an isomorphous derivative, in which a bromine atom was attached to the 5 position of cytosine 8. Problems of fit between the search model and the structure ultimately obtained necessitated the use of Patterson correlation procedures between the determination of the orientation and the translation of the molecule. In all, 69 solvent molecules have been identified, and the structure has been refined to an R-factor of 0.214, using the 1421 reflections with F > 2sigma(F), collected at -120 degrees C. The sequence produces a molecule containing eight Watson-Crick base-pairs and a two-nucleotide 5'-sticky end at each end of the duplex. The sticky ends cohere with one another, so the molecules form continuous 10-fold double helices throughout the crystal, with each strand being interrupted by inherent staggered nicks. The relative angular relationships between helices in the structure differ from each other; most of the arrangements differ from Holliday junctions, whose rotational orientations are phased by a crossover and which are modeled to contain double helices that are exactly parallel or antiparallel. However, one helical juxtaposition in this crystal is similar to the alignment of double helices in parallel Holliday junctions. A survey of DNA decamers that also form infinite helices in crystals reveals relationships that approximate both parallel and antiparallel Holliday junction alignments.

Crystallography, X-Ray↗
PubMed1993

Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms.

The crystal structure of the Src SH2 domain complexed with a high affinity 11-residue phosphopeptide has been determined at 2.7 A resolution by X-ray diffraction. The peptide binds in an extended conformation and makes primary interactions with the SH2 domain at six central residues: PQ(pY)EEI. The phosphotyrosine and the isoleucine are tightly bound by two well-defined pockets on the protein surface, resulting in a complex that resembles a two-pronged plug engaging a two-holed socket. The glutamate residues are in solvent-exposed environments in the vicinity of basic side chains of the SH2 domain, and the two N-terminal residues cap the phosphotyrosine-binding site. The crystal structure of Src SH2 in the absence of peptide has been determined at 2.5 A resolution, and comparison with the structure of the high affinity complex reveals only localized and relatively small changes.

Amino Acid Sequence↗
PubMed1995

Molecular and crystal structures of two 1,6-anhydro-beta-maltotriose derivatives.

Crystal structures of two 1,6-anhydro-beta-maltotriose derivatives, 1,6-anhydro-beta-maltotriose nonaacetate and 6"-bromo-6"-deoxy-1,6-anhydro-beta-maltotriose octaacetate, have been determined. Both structures are isomorphous and belong to the orthorhombic system, space group of P2(1)2(1)2(1), with cell dimensions of a = 15.659(3) A, b = 20.587(6) A, c = 13.023(2) A and a = 15.402(7) A, b = 19.737(8) A, c = 13.481(5) A, respectively. Each molecule has three alpha-(1-->4)-linked glucose units, and two of them have a typical 4C1 chair conformation, while the glucose unit with the 1,6-anhydro bridge has a 1C4 chair-envelope intermediate conformation. In spite of introducing the 1,6-anhydro bridge and acetyl groups, the conformations of the glycosidic linkages in these molecules are almost the same as those of other alpha-(1-->4)-linked oligosaccharides. Crystal structures are stabilized by hydrophobic interactions and by a weak intermolecular hydrogen bond of C-H. . .O.

Acetates↗
PubMed1983

X-ray studies on crystalline complexes involving amino acids and peptides. X. Head-to-tail sequences in the crystal structure of L-lysine acetate.

L-Lysine acetate crystallises in the monoclinic space group P21 with a = 5.411 (1), b = 7.562(1), c = 12.635(2) A and beta = 91.7(1) degrees. The crystal structure was solved by direct methods and refined to an R value of 0.049 using the full matrix least squares method. The conformation and the aggregation of lysine molecules in the structure are similar to those found in the crystal structure of L-lysine L-aspartate. A conspicuous similarity between the crystal structures of L-arginine acetate and L-lysine acetate is that in both cases the strongly basic side chain, although having the largest pK value, interacts with the weakly acidic acetate group leaving the alpha-amino and the alpha-carboxylate groups to take part in head-to-tail sequences. These structures thus indicate that electrostatic effects are strongly modulated by other factors so as to give rise to head-to-tail sequences which have earlier been shown to be an almost universal feature of amino acid aggregation in the solid state.

Amino Acids↗
PubMed1995

Structure and function of cytochromes P450: a comparative analysis of three crystal structures.

BACKGROUND: Cytochromes P450 catalyze the oxidation of a variety of hydrophobic substrates. Sequence identities between P450 families are generally low (10-30%), and consequently, the structure-function correlations among P450s are not clear. The crystal structures of P450terp and the hemoprotein domain of P450BM-3 were recently determined, and are compared here with the previously available structure of P450cam. RESULTS: The topology of all three enzymes is quite similar. The heme-binding core structure is well conserved, except for local differences in the I helices. The greatest variation is observed in the substrate-binding regions. The structural superposition of the proteins permits an improved sequence alignment of other P450s. The charge distribution in the three structures is similarly asymmetric and defines a molecular dipole. CONCLUSIONS: Based on this comparison we believe that all P450s will be found to possess the same tertiary structure. The ability to precisely predict other P450 substrate-contact residues is limited by the extreme structural heterogeneity in the substrate-recognition regions. The central I-helix structures of P450terp and P450BM-3 suggest a role for helix-associated solvent molecules as a source of catalytic protons, distinct from the mechanism for P450cam. We suggest that the P450 molecular dipole might aid in both redox-partner docking and proton recruitment for catalysis.

Amino Acid Sequence↗
PubMed2001

Crystal structure of unligated guanylate kinase from yeast reveals GMP-induced conformational changes.

The crystal structure of guanylate kinase (GK) from yeast (Saccharomyces cerevisiae) with a non-acetylated N terminus has been determined in its unligated form (apo-GK) as well as in complex with GMP (GK.GMP). The structure of apo-GK was solved with multiwavelength anomalous diffraction data and refined to an R-factor of 0.164 (R(free)=0.199) at 2.3 A resolution. The structure of GK.GMP was determined using the crystal structure of GK with an acetylated N terminus as the search model and refined to an R-factor of 0.156 (R(free)=0.245) at 1.9 A. GK belongs to the family of nucleoside monophosphate (NMP) kinases and catalyzes the reversible phosphoryl transfer from ATP to GMP. Like other NMP kinases, GK consists of three dynamic domains: the CORE, LID, and NMP-binding domains. Dramatic movements of the GMP-binding domain and smaller but significant movements of the LID domain have been revealed by comparing the structures of apo-GK and GK.GMP. apo-GK has a much more open conformation than the GK.GMP complex. Systematic analysis of the domain movements using the program DynDom shows that the large movements of the GMP-binding domain involve a rotation around an effective hinge axis approximately parallel with helix 3, which connects the GMP-binding and CORE domains. The C-terminal portion of helix 3, which connects to the CORE domain, has strikingly higher temperature factors in GK.GMP than in apo-GK, indicating that these residues become more mobile upon GMP binding. The results suggest that helix 3 plays an important role in domain movement. Unlike the GMP-binding domain, which moves toward the active center of the enzyme upon GMP binding, the LID domain moves away from the active center and makes the presumed ATP-binding site more open. Therefore, the LID domain movement may facilitate the binding of MgATP. The structure of the recombinant GK.GMP complex superimposes very well with that of the native GK.GMP complex, indicating that N-terminal acetylation does not have significant impact on the three-dimensional structure of GK.

Acetylation↗
PubMed1997

Synthetic, structural and biological studies of the ubiquitin system: synthesis and crystal structure of an analogue containing unnatural amino acids.

Ubiquitin is a 76-amino acid protein involved in the targeting for destruction of proteins in the cell. The protein can readily be synthesized chemically affording an extra dimension to studies of protein stability. Ubiquitin with various modifications to the hydrophobic core has been synthesized. In particular, two core amino acids have been replaced by aminobutyric acid (Val-26) and norvaline (for Ile-30) and the product crystallized. The refined crystal structure shows an overall contraction of the molecule and the side chain of Nva-30 rotates relative to Ile-30. However, the side chain rotation is not sufficient to compensate for the effect of the loss of the methyl group and hence a small cavity is introduced into the structure, which decreases the stability of the protein. The biological behaviour of the modified protein is unaltered. The observed changes in stability are of the magnitude expected for the removal of methyl groups from the hydrophobic core of a protein. Interestingly, the effect appears to be independent of the position of the removed methyl group. The intact structure, but not its stability, is important for recognition by the biological conjugating system.

Aminobutyrates↗
PubMed2005

Insights into the structural determinants of cohesin-dockerin specificity revealed by the crystal structure of the type II cohesin from Clostridium thermocellum SdbA.

The plant cell wall degrading enzymes expressed by anaerobic microorganisms form large multienzyme complexes (cellulosomes). Cellulosomes assemble by the Type I dockerins on the catalytic subunits binding to the reiterated Type I cohesins in the molecular scaffold, while Type II dockerin-cohesin interactions anchor the complex onto the bacterial cell surface. Type I and Type II cohesin, dockerin pairs show no cross-specificity. Here we report the crystal structure of the Type II cohesin (CohII) from the Clostridium thermocellum cell surface anchoring protein SdbA. The protein domain contains nine beta-strands and a small alpha-helix. The beta-strands assemble into two elongated beta-sheets that display a typical jelly roll fold. The structure of CohII is very similar to Type I cohesins, and the dockerin binding site, which is centred at beta-strands 3, 5 and 6, is likely to be conserved in the two proteins. Subtle differences in the topology of the binding sites and a lack of sequence identity in the beta-strands that comprise the core of the dockerin binding site explain why Type I and Type II cohesins display such distinct specificities for their target dockerins.

Amino Acid Sequence↗
PubMed1994

Crystal structure of cholesteryl butanoate at 123 K.

Cholesteryl butanoate has a complex crystal structure that differs from those of the three main structure type for cholesteryl esters. It contains four molecules (C31H52O2) unrelated by crystal symmetry. The molecules are packed in almost planar sheets and have molecular long axes nearly parallel. However, the molecules have different orientations about their long axes and furthermore, in a given sheet, one of the independent molecules is antiparallel to the other three. Viewed down the molecular long axes, each molecule has six nearest neighbors, but the detailed environment is different for the four independent molecules. Thus the molecular arrangement has features that are characteristic of the short-range order present in the cholesteric mesophase. The monotropic transformation from the crystalline to the cholesteric phase occurs at 98 degrees C. The crystal structure has been accurately determined using 12,146 independent X-ray reflections having sin theta/lambda < 0.63 A-1. All hydrogen atoms were located from a difference Fourier and were included in a refinement that gave R(F2) = 0.064. The C-C bond lengths have sigma = 0.003 A and C-C-C bond angles have sigma = 0.2 degrees. Conformations for the steroid ring system are similar but there are differences in the C17 side chains and the butanoate chains of the four independent molecules. Analysis of atomic m.s. displacement tensors using a segmented-body model indicates that there are internal librations involving both the C17 and butanoate chains in all molecules.

Cholesterol Esters↗
PubMed1995

The crystal structure of human endothelin-1 and how it relates to receptor binding.

Several different three-dimensional structures have recently been proposed for human endothelin-1 (ET-1) based on x-ray crystallographic, NMR spectroscopic, and modeling studies. All differ considerably in the regions that are critical for receptor binding, i.e., the central loop and the C-terminal tail, which is helical in the crystal structure but not helical in any of the other structures. In this study we examined the various ET structures in light of binding and vasoactivity data available for naturally occurring isoforms and synthetic mutants of ET. These studies strongly support the crystal structure alone as being biologically relevant with respect to receptor binding. Furthermore, molecular modeling studies based on the crystal structure of ET-1 have produced models for the ET-2 and ET-3 isoforms that suggest geometric properties for the receptor selectivity pocket of the ET(A) receptor. From these studies, it appears that the crystal structure may prove useful for aiding our understanding of the nature of the receptor/ligand binding sites and for providing a basis for the design of new agonists and antagonists.

Binding Sites↗
PubMed2002

Crystallisation under microgravity of mistletoe lectin I from Viscum album with adenine monophosphate and the crystal structure at 1.9 A resolution.

The crystal structure of the ribosome-inactivating protein (RIP) mistletoe lectin I (ML-I) from Viscum album in complex with adenine has been refined to 1.9 A resolution. High quality crystals of the ML-I complex were obtained by the method of vapour diffusion using the high density protein crystal growth system (HDPCG) on the international space station, mission ISS 6A. Hexagonal crystals were grown during three months under microgravity conditions. Diffraction data to 1.9A were collected applying synchrotron radiation and cryo- techniques. The structure was refined subsequently to analyse the structure of ML-I and particularly the active site conformation, complexed by adenine that mimics the RNA substrate binding.

Adenosine Monophosphate↗
PubMed1994

Energy calculations and analysis of HIV-1 protease-inhibitor crystal structures.

The interactions between HIV-1 protease and its bound inhibitors have been investigated by molecular mechanics calculations and by analysis of crystal structures of the complexes in order to determine general rules for inhibitor and substrate binding to the protease. Fifteen crystal structures of HIV-1 protease with different peptidomimetic inhibitors showed conservation of hydrogen bond interactions between the main chain C = O and NH groups of the inhibitors and the C = O and NH groups of the protease extending from P3 C = O to P3' NH. The mean length of the hydrogen bonds between the inhibitor and the flexible flaps and the conserved water molecule (2.9 A) is slightly shorter than the mean length of hydrogen bonds between the inhibitor and the more rigid active site region (3.1 A) of the protease. The two hydrogen bonds between the conserved water and P2 and P1' carbonyl oxygen atoms of the inhibitor are the shortest and are predicted to be important for the tight binding of inhibitors. Molecular mechanics analysis of three crystal structures of HIV-1 protease with different inhibitors with independent calculations using the programs Discover and Brugel gave an estimate of 56-68% for the contribution of all the inhibitor main chain atoms to the total calculated protease-inhibitor interaction energy. The contribution of individual inhibitor residues to the interaction energy was calculated using Brugel. The main chain atoms of residue P2 had a consistently large favorable contribution to the total interaction energy, probably due to the presence of the two short hydrogen bonds to the flexible flap.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2005

Crystal structures, anisotropic growth, and optical properties: controlled synthesis of lanthanide orthophosphate one-dimensional nanomaterials.

The fundamental understanding of the relationship between crystal structure and the dynamic processes of anisotropic growth on the nanoscale, and exploration of the key factors governing the evolution of physical properties in functional nanomaterials, have become two of the most urgent and challenging issues in the fabrication and exploitation of functional nanomaterials with designed properties and the development of nanoscale devices. Herein, we show how structural and kinetic factors govern the tendency for anisotropic growth of such materials under hydrothermal conditions, and how the crystal structure and morphology influence the optical properties of Ln3+-doped nanocrystals. The synthesis of phase-pure and single-crystalline monoclinic, hexagonal, and tetragonal one-dimensional LnPO4 nanostructures of different aspect ratios by means of kinetically controlled hydrothermal growth processes is demonstrated. It is shown that the tendency for anisotropic growth under hydrothermal conditions can be enhanced simply by modifying the chemical potentials of species in the reaction solution through the use of carefully selected chelating ligands. A systematic study of the photoluminescence of various Eu3+-doped lanthanide phosphates has revealed that the optical properties of these nanophosphors are strongly dependent on their crystal structures and morphologies.

Journal Article↗
PubMed1990

Crystal structure of low humidity tetragonal lysozyme at 2.1-A resolution. Variability in hydration shell and its structural consequences.

Tetragonal crystals of hen egg white lysozyme undergo a reversible transformation, accompanied by loss of water, when the relative humidity of the environment is reduced to about 90%. The structure of the low humidity form has been analyzed, using x-ray data collected at 88% relative humidity, in order to explore the variability in protein hydration caused by a change in the amount of water surrounding the protein molecule and the consequent conformational perturbations in the molecule. The structure has been refined by the restrained least-squares method to an R value of 0.162 for 6269 observed reflections in the 10-2.1-A resolution shell. The refined structure provides interesting examples for the variability in helical parameters, the role of interactions involving side chains and water in the stabilization of secondary structural features, and favorable specific hydration sites. The protein molecule as a whole moves slightly in the low humidity form from its position in the native crystals. The hydration shell tends to move along with the protein. Significant changes, however, occur in the hydration shell. These changes cause structural perturbations in the enzyme molecule, which are most pronounced in regions involved in substrate binding.

Animals↗