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PubMed1975

Structural studies of metabolic products of dopamine. IV. Crystal and molecular structure of (-)-noradrenaline.

The crystal structure of (-)-noradrenaline has been determined by X-ray methods, using 1000 observed reflections collected by counter diffractometer techniques. The crystals are orthorhombic, space group P212121, with a=8.611(2), B=6.138(2), And c=14.912(4) A. Least-squares refinements yielded a conventional R-factor of 0.036. Standard deviations in bond lengths are 0.003 A and in bond angles 0.2 degrees. The crystal structure of (-)-noradrenaline corresponds closely to that of (-)-adrenaline in molecular geometry, conformation, and arrangement in the crystals. The results of the structure investigations are discussed in relation to the biological activity of these biogenic amines.

Chemical Phenomena↗
PubMed1989

A new group of antibiotics, hydroxamic acid antimycotic antibiotics. II. The structure of neoenactins NL1 and NL2 and structure-activity relationship.

The structures of neoenactins (NEs) NL1 and NL2, novel antimycotic antibiotics produced by Streptoverticillium olivoreticuli in a precursor-oriented fashion, were elucidated by 1H and 13C NMR and mass spectroscopic studies. The structures of both antibiotics are closely related to that of NE-A, the major component of NE congeners, being classified in the group of hydroxamic acid antimycotic antibiotics in which L-serine and a diketo amine form a hydroxamic acid structure. To study the role of the carbonyl groups in the biological activities of the hydroxamic acid antimycotic antibiotics, NE-A was modified by reaction with various carbonyl reagents. In terms of antimycotic activity, the derivatives are classified into two distinct groups; the first ones are fairly comparable to but not exceeding and the second ones are less active than NE-A depending on their tendency to revert to NE-A by hydrolysis. In general, the biological activities of the derivatives are inversely proportional to their stabilities to hydrolysis.

Antifungal Agents↗
PubMed1995

New metabolites with nematicidal and antimicrobial activities from the ascomycete Lachnum papyraceum (Karst.) Karst. VI. Structure determination of non-halogenated metabolites structurally related to mycorrhizin A.

The structure determination of four new biologically active non-halogenated metabolites isolated from submerged cultures of the ascomycete Lachnum papyraceum is described. The compounds are structurally related to the antibiotic mycorrhizin A: (l'Z)-Dechloromycorrhizin A (12), a stereoisomer of dechloromycorrhizin A (5) previously isolated from the same fungus, as well as papyracon A (13), papyracon B (14) and papyracon C (15) containing an exocyclic double bond. The amounts of the latter three increased significantly when CaBr2 was added to the culture medium. The structures were determined by spectroscopic methods.

Anti-Bacterial Agents↗
PubMed1999

Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains.

The endothelial cell protein C/activated protein C receptor (EPCR) is located primarily on the surface of the large vessels of the vasculature. In vitro studies suggest that it is involved in the protein C anticoagulant pathway. We report the organization and nucleotide sequence of the human EPCR gene. It spans approximately 6 kbp of genomic DNA, with a transcription initiation point 79 bp upstream of the translation initiation (Met) codon in close proximity to a TATA box and other promoter element consensus sequences. The human EPCR gene has been localized to 20q11.2 and consists of four exons interrupted by three introns, all of which obey the GT-AG rule. Exon I encodes the 5' untranslated region and the signal peptide, and exon IV encodes the transmembrane domain, the cytoplasmic tail, and the 3' untranslated region. Exons II and III encode most of the extracellular region of the EPCR. These exons have been found to correspond to those encoding the alpha1 and alpha2 domains of the CD1/major histocompatibility complex (MHC) class I superfamily. Flanking and intervening introns are of the same phase (phase I) and the position of the intervening intron is identically located. Secondary structure prediction for the amino acid sequence of exons II and III corresponds well with the actual secondary structure elements determined for the alpha1 and alpha2 domains of HLA-A2 and murine CD1.1 from crystal structures. These findings suggest that the EPCR folds with a beta-sheet platform supporting two alpha-helical regions collectively forming a potential binding pocket for protein C/activated protein C.

Amino Acid Sequence↗
PubMed2002

The analysis of structure-anticancer and antiviral activity relationships for macrocyclic pyridinophanes and their analogues on the basis of 4D QSAR models (simplex representation of molecular structure).

A new 4D-QSAR approach has been considered. For all investigated molecules the 3D structural models have been created and the set of conformers (fourth dimension) have been used. Each conformer is represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry). The investigation of influence of molecular structure of macrocyclic pyridinophanes, their analogues and certain other compounds on anticancer and antiviral (anti-influenza, antiherpes and antiadenovirus) activity has been carried out by means of the 4D-QSAR. Statistic characteristics for QSAR of PLS (partial least squares) models are satisfactory (R = 0.92-0.97; CVR = 0.63-0.83). Molecular fragments increasing and decreasing biological activity were defined. This information may be useful for design, and direct synthesis of novel anticancer and antiviral agents.

Antineoplastic Agents↗
PubMedDate not supplied

["Bridge" structures between nucleic acid molecules fixed in the structure of a liquid crystal].

The binding of daunomycin and copper ions to poly(I).poly(C) molecules fixed in a particle of a liquid-crystalline dispersion was studied. A thermodynamic model of adsorption was developed, which makes it possible to describe the formation of complexes of a particular kind, "bridges" that connect adjacent nucleic acid molecules fixed in a liquid crystal. The bridges represent chelate complexes, which incorporate the molecules of the antibiotic daunomycin and copper ions. Equations describing the dependence of the concentration of these bridges in solution on the concentration of their constituents were derived. The family of dependences of experimental amplitudes of bands in CD spectra typical of "bridge" structures on the concentration of copper ions represents a set of S-shaped curves, and, as the concentration of daunomycin in solution increases, the level of saturation of these curves increases. The analysis of experimental data with the use of this model suggests that the structures of this type compete with daunomycin molecules for the binding sites on poly(I).poly(C). By using this model, the energies of formation of bridge structures were calculated.

Adsorption↗
PubMed2006

Molecular and structural characterization of the domain 2 of hepatitis C virus non-structural protein 5A.

Hepatitis C virus (HCV) non-structural protein 5A protein (NS5A), which consists of three functional domains, is involved in regulating viral replication, interferon resistance, and apoptosis. Recently, the three-dimensional structure of the domain 1 was determined. However, currently the molecular basis for the domains 2 and 3 of HCV NS5A is yet to be defined. Toward this end, we expressed, purified the domain 2 of the NS5A (NS5A-D2), and then performed biochemical and structural studies. The purified domain 2 was active and was able to bind NS5B and PKR, biological partners of NS5A. The results from gel filtration, CD analysis, 1D 1H NMR and 2D 1H-15N heteronuclear single quantum correlation (HSQC) spectroscopy indicate that the domain 2 of NS5A appears to be flexible and disordered.

Amino Acid Sequence↗
PubMed1991

[PAF-antagonists with a phospholipid structure. 1. Phospholipids with hetero-arene head groups: synthesis, characterization and determination of the action of structural elements].

A series of analogues of platelet-activating factor (PAF) with heteroarene head groups have been synthesized, and tested for biological activities on blood platelets in vitro. In comparison with PAF most of the structural modifications exerted weak proaggregatory effects. The 4-(dimethylamino)pyridinium compound did not activate platelets but inhibited selectively PAF-induced platelet responses. These results point to a crucial role of the distance between the phosphoryl group and polar head for expression of PAF-antagonistic properties. Structural features of PAF-antagonist have been investigated by two-dimensional proton NMR spectroscopy, and proposed a model with three-dimensional structure.

Blood Platelets↗
PubMed1985

Molecular structure of Ro15-1788 and a model for the binding of benzodiazepine receptor ligands. Structural identification of common features in antagonists.

Ligands that bind to the benzodiazepine receptor have three possible effects. The ligand can be an agonist and reduce anxiety, an antagonist and have no biological effect, or an inverse agonist and promote convulsions. This receptor complex is unique in its spectrum of response to ligands, and conformational changes in the receptor are implicated. The x-ray crystal structure of an imidazobenzodiazepine antagonist ligand, Ro15-1788, was determined and compared to the structures of the 1,4-benzodiazepine agonists and to two other types of antagonists, beta-carbolines and a pyrazoloquinolinone, CGS-8216. The antagonists were found to have similar arrangements of binding features including an aromatic ring, a carbonyl oxygen atom, and a hydrophobic side chain. The structures of these antagonists could be superimposed in a model binding site with three common features for all of the antagonists and a fourth hydrogen-bonding site for the pure antagonists (or inverse agonists), the beta-carbolines, and CGS-8216. A comparison of the shapes of the antagonist benzodiazepine, Ro15-1788, and several agonists showed that RO15-1788 has a unique azepine ring conformation that distorts the usual arrangement of the aromatic A ring, carbonyl oxygen atom, and imine N atom of the agonists. A conformational adjustment in the receptor would be required to accommodate both of these types of ligands. A summary of the superpositions of typical agonists and the antagonists leads to a model with 7 conformationally mobile binding points. Inverse agonists are distinguished from antagonists by the length of the hydrophobic side chain. Antagonists are distinguished from agonists in part by the lack of a binding feature similar to the imine N atom of the diazepine ring. This model accounts for the key features found in ligands for the benzodiazepine receptor and provides an explanation for the spectrum of responses elicited by receptor binding.

Benzodiazepinones↗
PubMed1980

Receptor interactions of imidazolines. IV. Structural requirements for alpha adrenergic receptor occupation and receptor activation by clonidine and a series of structural analogs in rat aorta.

Clonidine and a series of nine halogen and alkyl-substituted structural analogs were evaluated for alpha adrenergic receptor agonist activity in rat aorta. Phenylephrine was included for comparison. All the imidazolines were partial agonists with respect to phenylephrine due to the fact that they only weakly activated the receptor. Whereas phenylephrine requires approximately 0.2% receptor occupancy to produce a response 20% of maximum, the imidazolines required from 25 to 100% receptor occupancy to produce the same response. Although clonidine and its structural analogs are from 125 to 500 times weaker activators of the alpha adrenergic receptor than phenylephrine, they have from 2 to 60 times higher affinity for the receptor than phenylephrine. The results support our previous conclusions that a dichotomy exists between the factors that direct receptor occupation and receptor activation since the structural requirements for each of these parameters differ.

Adrenergic alpha-Agonists↗
PubMed1994

Crystal structures, spectroscopic features, and catalytic properties of cobalt(II), copper(II), nickel(II), and mercury(II) derivatives of the zinc endopeptidase astacin. A correlation of structure and proteolytic activity.

The catalytic zinc ion of astacin, a prototypical metalloproteinase from crayfish, has been substituted by Co(II), Cu(II), Hg(II), and Ni(II) in order to probe the role of the metal for both catalysis and structure. Compared to Zn(II)-astacin, Co(II)- and Cu(II)-astacin display enzymatic activities of about 140 and 37%, respectively, while Ni(II)- and Hg(II)-astacin are almost inactive. The electron paramagnetic resonance spectrum of Cu(II)-astacin is typical of 5-fold coordinated copper(II), and its intense absorption maxima at 445 and 325 nm are probably due to ligand-metal charge-transfer transitions involving Tyr-149. This residue had been identified previously by x-ray crystallography of the zinc enzyme as a zinc ligand, in addition to three imidazoles and a glutamic acid-bound water molecule. We present now the refined high-resolution x-ray crystal structures of Cu(II)-, Co(II)-, and Ni(II)-astacin, which exhibit a virtually identical protein framework to the previously analyzed structures of Zn(II)-, apo-, and Hg(II)-astacin. In Co(II)- and Cu(II)-astacin, the metal is penta-coordinated similarly to the native zinc enzyme. In the Ni(II) derivative, however, an additional solvent molecule expands the metal coordination sphere to a distorted octahedral ligand geometry, while in Hg(II)-astacin, no ordered solvent molecule at all is observed in the inner coordination sphere of the metal. This indicates a close correlation between catalytic properties and ground-state metal coordination of astacin.

Amino Acid Sequence↗
PubMed1993

Peptide mimics for structural features in proteins. Crystal structures of three heptapeptide helices with a C-terminal 6-->1 hydrogen bond.

The crystal structure determination of three heptapeptides containing alpha-aminoisobutyryl (Aib) residues as a means of helix stabilization provides a high-resolution characterization of 6-->1 hydrogen-bonded conformations, reminiscent of helix-terminating structural features in proteins. The crystal parameters for the three peptides, Boc-Val-Aib-X-Aib-Ala-Aib-Y-OMe, where X and Y are Phe, Leu (I), Leu, Phe (II) and Leu, Leu (III) are: (I) space group P1, Z = 1, a = 9.903 A, b = 10.709 A, c = 11.969 A, alpha = 102.94 degrees, beta = 103.41 degrees, gamma = 92.72 degrees, R = 4.55%; (II) space group P21, Z = 2, a = 10.052 A, b = 17.653 A, c = 13.510 A, beta = 108.45 degrees, R = 4.49%; (III) space group P1, Z = 2 (two independent molecules IIIa and IIIb in the asymmetric unit), a = 10.833 A, b = 13.850 A, c = 16.928 A, alpha = 99.77 degrees, beta = 105.90 degrees, gamma = 90.64 degrees, R = 8.54%. In all cases the helices form 3(10)/alpha-helical (or 3(10)helical) structures, with helical columns formed by head-to-tail hydrogen bonding. The helices assemble in an all-parallel motif in crystals I and III and in an antiparallel motif in II. In the four crystallographically characterized molecules, I, II, IIIa and IIIb, Aib(6) adopts a left-handed helical (hL) conformation with positive phi, psi values, resulting in 6-->1 hydrogen-bond formation between Aib(2) CO and Leu(7)/Phe(7) NH groups. In addition a 4-->1 hydrogen bond is seen between Aib(3) CO and Aib(6) NH groups. This pattern of hydrogen bonding is often observed at the C-terminus of helices proteins, with the terminal pi-type turn being formed by four residues adopting the hRhRhRhL conformation.

Amino Acid Sequence↗
PubMed1993

Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.

A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional structure determination. The initial compound, haloperidol, was discovered through computational screening of the Cambridge Structural Database using a shape complementarity algorithm. The subsequent modification is a non-peptidic lateral lead, which belongs to a family of compounds with well characterized pharmacological properties. This thioketal derivative of haloperidol and a halide counterion are bound within the enzyme active site in a mode distinct from the observed for peptide-based inhibitors. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based search. The structures provide the context for subsequent synthetic modifications of the inhibitor.

Binding Sites↗
PubMed1993

[PAF-antagonists with a phospholipid structure. 5. Propanediol phospholipids with various substituted pyridinium and quinuclidinium head groups and variations of the phosphorus-nitrogen distance;synthesis, characterization and structure activity relationship].

A series of 10 PAF-analogues, structurally modified in position C-2 (n-propyl) and position C-3 (polar head group) were synthesized, and the PAF-inhibitory potencies was evaluated using PAF-induced aggregation of human blood platelets in vitro. Structure-activity relationships revealed, that the PAF-inhibitory activity is strongly influenced by the distance between phosphate and onium center and the structure of the substituted heterocyclus. The best activity was observed by 3,5-dimethylpyridinium- and 4-ethylpyridinium derivative with a P-N-distance of 6 methylene groups (IC50 = 1.9 x 10(-6) mol/l and 2.7 x 10(-6) mol/l).

Blood Platelets↗
PubMed1995

[Fine stereo structure for natural organic molecules, a preliminary study. II. Melting point influenced by structure factors].

Crystal structures of two compounds from Tripterygium wilfordii Hook f. have been determined by X-ray diffraction method. Structure factors influencing melting point of solid state have been analysed. Crystal class (or space group), recrystallization solvent, force between molecules and fine changes of molecular structures will all cause melting point changes of crystal substance.

Crystallography, X-Ray↗
PubMed1996

Solution structure of P01, a natural scorpion peptide structurally analogous to scorpion toxins specific for apamin-sensitive potassium channel.

The venom of the North African scorpion Androctonus mauretanicus mauretanicus possesses numerous highly active neurotoxins that specifically bind to various ion channels. One of these, P05, has been found to bind specifically to calcium-activated potassium channels and also to compete with apamin, a toxin extracted from bee venom. Besides the highly potent ones, several of these peptides (including that of P01) have been purified and been found to possess only a very weak, although significant, activity in competition with apamin. The amino acid sequence of P01 shows that it is shorter than P05 by two residues. This deletion occurs within an alpha-helix stretch (residues 5-12). This alpha-helix has been shown to be involved in the interaction of P05 with its receptor via two arginine residues. These two arginines are absent in the P01 sequence. Furthermore, a proline residue in position 7 of the P01 sequence may act as an alpha-helix breaker. We have determined the solution structure of P01 by conventional two-dimensional 1H nuclear magnetic resonance and show that 1) the proline residue does not disturb the alpha-helix running from residues 5 to 12; 2) the two arginines are topologically replaced by two acidic residues, which explains the drop in activity; 3) the residual binding activity may be due to the histidine residue in position 9; and 4) the overall secondary structure is conserved, i.e., an alpha-helix running from residues 5 to 12, two antiparallel stretches of beta-sheet (residues 15-20 and 23-27) connected by a type I' beta-turn, and three disulfide bridges connecting the alpha-helix to the beta-sheet.

Amino Acid Sequence↗
PubMed2005

Does secondary structure determine tertiary structure in proteins?

Is highly approximate knowledge of a protein's backbone structure sufficient to successfully identify its family, superfamily, and tertiary fold? To explore this question, backbone dihedral angles were extracted from the known three-dimensional structure of 2,439 proteins and mapped into 36 labeled, 60 degrees x 60 degrees bins, called mesostates. Using this coarse-grained mapping, protein conformation can be approximated by a linear sequence of mesostates. These linear strings can then be aligned and assessed by conventional sequence-comparison methods. We report that the mesostate sequence is sufficient to recognize a protein's family, superfamily, and fold with good fidelity.

Algorithms↗
PubMed2000

Crystal structure of cancer chemopreventive Bowman-Birk inhibitor in ternary complex with bovine trypsin at 2.3 A resolution. Structural basis of Janus-faced serine protease inhibitor specificity.

Understanding molecular recognition on a structural basis is an objective with broad academic and applied significance. In the complexes of serine proteases and their proteinaceous inhibitors, recognition is governed mainly by residue P1 in accord with primary serine protease specificity. The bifunctional soybean Bowman-Birk inhibitor (sBBI) should, therefore, interact at LysI16 (subdomain 1) with trypsin and at LeuI43 (subdomain 2) with chymotrypsin. In contrast with this prediction, a 2:1 assembly with trypsin was observed in solution and in the crystal structure of sBBI in complex with trypsin, determined at 2.3 A resolution by molecular replacement. Strikingly, P1LeuI43 of sBBI was fully embedded into the S(1) pocket of trypsin in contrast to primary specificity. The triple-stranded beta-hairpin unique to the BBI-family and the surface loops surrounding the active site of the enzyme formed a protein-protein-interface far extended beyond the primary contact region. Polar residues, hydrophilic bridges and weak hydrophobic contacts were predominant in subdomain 1, interacting specifically with trypsin. However, close hydrophobic contacts across the interface were characteristic of subdomain 2 reacting with both trypsin and chymotrypsin. A Met27Ile replacement shifted the ratio with trypsin to the predicted 1:1 ratio. Thus, the buried salt-bridge responsible for trypsin specificity was stabilised in a polar, and destabilized in a hydrophobic, environment. This may be used for adjusting the specificity of protease inhibitors for applications such as insecticides and cancer chemopreventive agents.

Amino Acid Sequence↗