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- Biochemie und Chemie (31) (remove)
Type I interferons (IFNs) signal for their diverse biological effects by binding a common receptor on target cells, composed of the two transmembrane IFNAR1 and IFNAR2 proteins. We have previously differentially enhanced the antiproliferative activity of IFN by increasing the weak binding affinity of IFN to IFNAR1. In this study, we further explored the affinity interdependencies between the two receptor subunits and the role of IFNAR1 in differential IFN activity. For this purpose, we generated a panel of mutations targeting the IFNAR2 binding site on the background of the IFNalpha2 YNS mutant, which increases the affinity to IFNAR1 by 60-fold, resulting in IFNAR2-to-IFNAR1 binding affinity ratios ranging from 1000:1 to 1:1000. Both the antiproliferative and antiviral potencies of the interferon mutants clearly correlated to the in situ binding IC(50) values, independently of the relative contributions of the individual receptors, thus relating to the integral lifetime of the complex. However, the antiproliferative potency correlated throughout the entire range of affinities, as well as with prolonged IFNAR1 receptor down-regulation, whereas the antiviral potency reached a maximum at binding affinities equivalent to that of wild-type IFNalpha2. Our data suggest that (i) the specific activity of interferon is related to the ternary complex binding affinity and not to affinity toward individual receptor components and (ii) although the antiviral pathway is strongly dependent on pSTAT1 activity, the cytostatic effect requires additional mechanisms that may involve IFNAR1 down-regulation. This differential interferon response is ultimately mediated through distinct gene expression profiling.
The neuronal adaptor protein Fe65 is involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP. It contains three protein-protein interaction domains, one WW domain, and a unique tandem array of phosphotyrosine-binding (PTB) domains. The N-terminal PTB domain (Fe65-PTB1) was shown to interact with a variety of proteins, including the low density lipoprotein receptor-related protein (LRP-1), the ApoEr2 receptor, and the histone acetyltransferase Tip60. We have determined the crystal structures of human Fe65-PTB1 in its apo- and in a phosphate-bound form at 2.2 and 2.7A resolution, respectively. The overall fold shows a PTB-typical pleckstrin homology domain superfold. Although Fe65-PTB1 has been classified on an evolutionary basis as a Dab-like PTB domain, it contains attributes of other PTB domain subfamilies. The phosphotyrosine-binding pocket resembles IRS-like PTB domains, and the bound phosphate occupies the binding site of the phosphotyrosine (Tyr(P)) within the canonical NPXpY recognition motif. In addition Fe65-PTB1 contains a loop insertion between helix alpha2 and strand beta2(alpha2/beta2 loop) similar to members of the Shc-like PTB domain subfamily. The structural comparison with the Dab1-PTB domain reveals a putative phospholipid-binding site opposite the peptide binding pocket. We suggest Fe65-PTB1 to interact with its target proteins involved in translocation and signaling of APP in a phosphorylation-dependent manner.
Cytotoxic T lymphocytes eliminate infected cells upon surface display of antigenic peptides on major histocompatibility complex I molecules. To promote immune evasion, UL49.5 of several varicelloviruses interferes with the pathway of major histocompatibility complex I antigen processing. However, the inhibition mechanism has not been elucidated yet. Within the macromolecular peptide-loading complex we identified the transporter associated with antigen processing (TAP1 and TAP2) as the prime target of UL49.5. Moreover, we determined the active oligomeric state and crucial elements of the viral factor. Remarkably, the last two residues of the cytosolic tail of UL49.5 are essential for endoplasmic reticulum (ER)-associated proteasomal degradation of TAP. However, this process strictly requires additional signaling of an upstream regulatory element in the ER lumenal domain of UL49.5. Within this new immune evasion mechanism, we show for the first time that additive elements of a small viral factor and their signaling across the ER membrane are essential for targeted degradation of a multi-subunit membrane complex.
Location and orientation of serotonin receptor 1a agonists in model and complex lipid membranes
(2008)
Magic angle spinning (MAS) NMR has been used to investigate the location and orientation of five serotonin receptor 1a agonists (serotonin, buspirone, quipazine, 8-OH-DPAT, and LY-163,165) in single component model lipid and brain lipid membranes. The agonist locations are probed by monitoring changes in the lipid proton chemical shifts and by MAS-assisted nuclear Overhauser enhancement spectroscopy, which indicates the orientation of the agonists with respect to the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids. In the single component bilayer, the membrane agonists are found predominantly in the top of the hydrophobic chain or in the glycerol region of the membrane. Most of the agonists orient approximately parallel to the membrane plane, with the exception of quipazine, whose piperazine ring is found in the glycerol region, whereas its benzene ring is located within the lipid hydrophobic chain. The location of the agonist in brain lipid membranes is similar to the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers; however, many of the agonists appear to locate close to the cholesterol in the membrane in preference to the phospholipids.
Mitochondrial complex I (NADH:ubiquinone oxidoreductase) undergoes reversible deactivation upon incubation at 30–37 °C. The active/deactive transition could play an important role in the regulation of complex I activity. It has been suggested recently that complex I may become modified by S-nitrosation under pathological conditions during hypoxia or when the nitric oxide:oxygen ratio increases. Apparently, a specific cysteine becomes accessible to chemical modification only in the deactive form of the enzyme. By selective fluorescence labeling and proteomic analysis, we have identified this residue as cysteine-39 of the mitochondrially encoded ND3 subunit of bovine heart mitochondria. Cysteine-39 is located in a loop connecting the first and second transmembrane helix of this highly hydrophobic subunit. We propose that this loop connects the ND3 subunit of the membrane arm with the PSST subunit of the peripheral arm of complex I, placing it in a region that is known to be critical for the catalytic mechanism of complex I. In fact, mutations in three positions of the loop were previously reported to cause Leigh syndrome with and without dystonia or progressive mitochondrial disease.
Chlamydia are obligate intracellular bacteria that cause variety of human diseases. Host cells infected with Chlamydia are protected against many different apoptotic stimuli. The induction of apoptosis resistance is thought to be an important immune escape mechanism allowing Chlamydia to replicate inside the host cell. Infection with C. trachomatis activates the Raf/MEK/ERK pathway and the PI3K/AKT pathway. Here we show that inhibition of these two pathways by chemical inhibitors sensitized C. trachomatis infected cells to granzyme B-mediated cell death. Infection leads to the Raf/MEK/ERK-mediated up-regulation and PI3K-dependent stabilization of the anti-apoptotic Bcl-2 family member Mcl-1. Consistently, interfering with Mcl-1 up-regulation sensitized infected cells for apoptosis induced via the TNF receptor, DNA damage, granzyme B and stress. Our data suggest that Mcl-1 up-regulation is primarily required to maintain apoptosis resistance in C. trachomatis-infected cells.
The title compound, C16H14N2O2, was derived from 1-(2-hydroxyphenyl)-3-(2-methoxyphenyl)propane-1,3-dione. The molecule is essentially planar (r.m.s. deviation for all non-H atoms = 0.089 Å). Two intramolecular hydrogen bonds stabilize the molecular conformation and one N-H...O hydrogen bond stabilizes the crystal structure. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; R factor = 0.035; wR factor = 0.091; data-to-parameter ratio = 9.3.
The title compound, [Fe2(C5H5)2(C24H22BP2)(CO)4][FeCl4]·CHCl3, is an oxidation product of CpFe(CO)2PPh2BH3. One pair of phenyl rings attached to the two different P atoms are almost parallel, as are the other pair [dihedral angles = 8.7 (5) and 8.9 (5)°]. The planes of the two cyclopentadienyl rings are inclined by 26.8 (7)° with respect to each other. The carbonyl groups at each Fe atom are almost perpendicular [C-Fe-C = 92.6 (6) and 94.3 (5)°]. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.019 Å; R factor = 0.112; wR factor = 0.177; data-to-parameter ratio = 16.8.
Geometric parameters of the title compound, C24H20N2O2S, are in the usual ranges. The central heterocycle makes dihedral angles of 41.29 (4) and 72.94 (5)° with the phenyl ring and the methoxyphenyl ring, respectively. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.038; wR factor = 0.103; data-to-parameter ratio = 14.1.
The title compound, [Re2(OH)(C10H8N2)2(CO)6][ReO4], is a mixed-valence rhenium compound containing discrete anions and cations. The ReI atoms are in a slightly distorted octahedral environment, whereas the ReVII atoms show the typical tetrahedral coordination mode. The dihedral angle between the two bipyridine groups is 34.3 (7)°. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.044 Å; R factor = 0.093; wR factor = 0.262; data-to-parameter ratio = 13.9.
In the title compound, C14H12N2O3, the dihedral angle between the two aromatic rings is 41.48 (5)°. The nitro group is twisted by 24.7 (3)° out of the plane of the aromatic ring to which it is attached. The molecules are connected by N-H...O hydrogen bonds into chains running along the alpha axis. Key indicators: single-crystal X-ray study; T = 273 K; mean σ(C–C) = 0.003 Å; R factor = 0.031; wR factor = 0.078; data-to-parameter ratio = 7.7.
Geometric parameters of the title compound, C14H12N2O4, are in the usual ranges. The dihedral angle between the two aromatic rings is 28.9 (1)°. The nitro group is twisted by 40.2 (1)° out of the plane of the aromatic ring to which it is attached. The crystal structure is stabilized by an N-H...O hydrogen bond. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.045; wR factor = 0.111; data-to-parameter ratio = 7.3.
Bromotriphenylsilane
(2008)
The title compound, C18H15BrSi, crystallizes with two almost identical molecules (r.m.s. deviation for all non-H atoms = 0.074 Å) in the asymmetric unit. It is isomorphous with chlorotriphenylsilane. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.010 Å; R factor = 0.095; wR factor = 0.288; data-to-parameter ratio = 17.0.
The complete molecule of the title compound, [Sn(C6H5)2Cl2(C9H21OP)2], is generated by crystallographic inversion symmetry, the Sn atom is located on a special position of site symmetry \overline{1}. The Sn atom adopts an all-trans SnC2O2Cl2 octahedral geometry. As a consequence of the bulky substituents at the O atom, the P-O-Sn bond angle is 163.9 (3)°. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.012 Å; R factor = 0.058; wR factor = 0.099; data-to-parameter ratio = 18.6.
The molecule of the title compound, C14H16N2O2, is located on a crystallographic twofold rotation axis. The central O-C-C-O bridge adopts a gauche conformation. One of the amine H atoms is disordered over two equally occupied positions. The crystal structure is stabilized by N-H...O and N-H...N hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; disorder in main residue; R factor = 0.049; wR factor = 0.119; data-to-parameter ratio = 17.9.
In the title compound, C27H16F6N2O6, the nitro groups are almost coplanar with the aromatic rings to which they are attached [dihedral angles = 3.5 (5) and 6.2 (3)°]. The dihedral angles between adjacent aromatic rings are 78.07 (8) and 71.11 (8)° for nitrophenyl/phenyl and 69.50 (8)° for phenyl/phenyl. An intermolecular C-H...[pi] interaction seems to be effective in the stabilization of the structure. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.045; wR factor = 0.092; data-to-parameter ratio = 12.5.
In the title compound, C12H14N22+·2Cl-, the 4,4'-dimethyl-2,2'-bipyridinium cation is essentially planar (r.m.s. deviation for all non-H atoms = 0.004 Å) and is located on a crystallographic inversion centre. The cations and chloride anions lie in planes parallel to (111) and are connected by N-H...Cl and C-H...Cl hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; R factor = 0.036; wR factor = 0.080; data-to-parameter ratio = 14.7.
The title compound, C15H14N2O4, is an important intermediate for the synthesis of thermotropic liquid crystals. The dihedral angle between the two aromatic rings is 84.29 (4)°. An N-H...O hydrogen bond connects the molecules into chains running along the b axis. In addition, the crystal packing is stabilized by weak C-H...O hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.036; wR factor = 0.096; data-to-parameter ratio = 14.3.
The absolute configuration of the title compound, [Fe(C5H5)(C36H29OP2)], is Sp at the ferrocene group and S at the asymmetric C atom. Both P atoms have a trigonal-pyramidal conformation. There is a short intramolecular C-H...P contact with an H...P distance of 2.56 Å. The hydroxy group is involved in an intramolecular O-H...[pi]phenyl interaction. The crystal packing shows five very weak intermolecular C-H...[pi] contacts, with H...Cg distances between 3.26 and 3.39 Å (Cg is the centroid of a phenyl or cyclopentadienyl ring). Key indicators: single-crystal X-ray study; T = 162 K; mean σ(C–C) = 0.004 Å; R factor = 0.038; wR factor = 0.083; data-to-parameter ratio = 22.3.
The absolute configuration of the title molecule, [Fe(C5H5)(C38H34NP2)]·CHCl3, is R,Rp. The molecular structure is similar to the structure of the solvent-free compound [Fukuzawa, Yamamoto & Kikuchi (2007). J. Org. Chem. 72, 1514-1517], but some torsion angles about the P-Cphenyl bonds differ by up to 25°. The P atoms and the N atom have a distorted trigonal-pyramidal geometry. The chloroform solvate group donates a C-H...[pi] bond to the central benzene ring and is also involved in six intermolecular C-H...Cl contacts with H...Cl distances between 2.96 and 3.13 Å. Key indicators: single-crystal X-ray study; T = 163 K; mean σ(C–C) = 0.003 Å; R factor = 0.039; wR factor = 0.088; data-to-parameter ratio = 24.2.
The geometric parameters of the molecule of the title compound, C14H16O2P2, are in the usual ranges. It is a meso compound with the two chiral P atoms having opposite configurations. The P-CH2-CH2-P chain adopts a trans conformation [torsion angle -178.59 (17)°]. The P=O bonds are almost coplanar with the adjacent phenyl ring [torsion angles = 3.8 (3) and 0.3 (3)°]. Whereas one of them is synclinal [torsion angle = -59.0 (2)°] to the central C-C bond, the other is anticlinal [torsion angle = 56.6 (2)°] to the central C-C bond. The dihedral angle between the two phenyl rings is 5.2 (3)°. The molecules are linked by weak C-H...O hydrogen bonds. They crystallize in rows running along the c axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.005 Å; R factor = 0.038; wR factor = 0.093; data-to-parameter ratio = 15.2.
In the title compound, C13H10N2O2, a Schiff base derivative, the dihedral angle between the two aromatic rings is 31.58 (3)°. The C=N double bond is essentially coplanar with the nitrophenyl ring. The torsion angle of the imine double bond is 175.97 (13)°, indicating that the C=N double bond is in a trans configuration. The crystal structure is stabilized by C-H...O contacts and [pi]-[pi] interactions (centroid-centroid distances of 3.807 and 3.808 Å). Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.034; wR factor = 0.093; data-to-parameter ratio = 10.3.
2-Aminopyrimidinium picrate
(2008)
The geometric parameters of the title compound, C4H6N3+·C6H2N3O7-, are in the usual ranges. While two nitro groups are almost coplanar with the aromatic picrate ring [dihedral angles 3.0 (2) and 4.4 (3)°], the third is significantly twisted out of this plane [dihedral angle 46.47 (8)°]. Anions and cations are connected via N-H...O hydrogen bonds. The molecules crystallize in planes parallel to (1\overline{2}1). Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.036; wR factor = 0.099; data-to-parameter ratio = 10.9.
The asymmetric unit of the title compound, C10H20I2Si2, contains two half-molecules. Both complete molecules are generated by crystallographic inversion centers located at the mid-points of the central C-C single bonds; the butadiene groups are planar, with a trans conformation about the central C-C bond. The molecules show short intramolecular H...I contacts of 2.89 and 2.92 Å. The crystal packing shows no short intermolecular contacts. Key indicators: single-crystal X-ray study; T = 155 K; mean σ(C–C) = 0.002 Å ; R factor = 0.021; wR factor = 0.059; data-to-parameter ratio = 43.6.
A mild synthetic method for N-formyl-Met-Leu-Phe-OH (1) is described. After Fmoc solid phase peptide synthesis, on-bead formylation and HPLC purification, more than 30 mg of the fully 13C/15N-labelled tripeptide 1 could be isolated in a typical batch. This peptide can be easily crystallised and is therefore well suited as a standard sample for setting up solid-state NMR experiments.
In a combined NMR/MD study, the temperature-dependent changes in the conformation of two members of the RNA YNMG-tetraloop motif (cUUCGg and uCACGg) have been investigated at temperatures of 298, 317 and 325 K. The two members have considerable different thermal stability and biological functions. In order to address these differences, the combined NMR/MD study was performed. The large temperature range represents a challenge for both, NMR relaxation analysis (consistent choice of effective bond length and CSA parameter) and all-atom MD simulation with explicit solvent (necessity to rescale the temperature). A convincing agreement of experiment and theory is found. Employing a principle component analysis of the MD trajectories, the conformational distribution of both hairpins at various temperatures is investigated. The ground state conformation and dynamics of the two tetraloops are indeed found to be very similar. Furthermore, both systems are initially destabilized by a loss of the stacking interactions between the first and the third nucleobase in the loop region. While the global fold is still preserved, this initiation of unfolding is already observed at 317 K for the uCACGg hairpin but at a significantly higher temperature for the cUUCGg hairpin.
A high-precision pressure probe is described which allows non-invasive online-monitoring of the water relations of intact leaves. Real-time recording of the leaf water status occurred by data transfer to an Internet server. The leaf patch clamp pressure probe measures the attenuated pressure, Pp, of a leaf patch in response to a constant clamp pressure, Pclamp. Pp is sensed by a miniaturized silicone pressure sensor integrated into the device. The magnitude of Pp is dictated by the transfer function of the leaf, Tf, which is a function of leaf patch volume and ultimately of cell turgor pressure, Pc, as shown theoretically. The power function Tf=f(Pc) theoretically derived was experimentally confirmed by concomitant Pp and Pc measurements on intact leaflets of the liana Tetrastigma voinierianum under greenhouse conditions. Simultaneous Pp recordings on leaflets up to 10 m height above ground demonstrated that changes in Tf induced by Pc changes due to changes of microclimate and/or of the irrigation regime were sensitively reflected in corresponding changes of Pp. Analysis of the data show that transpirational water loss during the morning hours was associated with a transient rise in turgor pressure gradients within the leaflets. Subsequent recovery of turgescence during the afternoon was much faster than the preceding transpiration-induced water loss if the plants were well irrigated. Our data show the enormous potential of the leaf patch clamp pressure probe for leaf water studies including unravelling of the hydraulic communication between neighbouring leaves and over long distances within tall plants (trees).
C2-symmetric bisamidines : chiral Brønsted bases catalysing the Diels-Alder reaction of anthrones
(2008)
C2-symmetric bisamidines 8 have been tested as chiral Brønsted bases in the Diels- Alder reaction of anthrones and N-substituted maleimides. High yields of cycloadducts and significant asymmetric inductions up to 76% ee are accessible. The proposed mechanism involves proton transfer between anthrone and bisamidine, association of the resulting ions and finally a cycloaddition step stereoselectively controlled by the chiral ion pair.
Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.
The degradation of the poly(A) tail is crucial for posttranscriptional gene regulation and for quality control of mRNA. Poly(A)-specific ribonuclease (PARN) is one of the major mammalian 3’ specific exo-ribonucleases involved in the degradation of the mRNA poly(A) tail, and it is also involved in the regulation of translation in early embryonic development. The interaction between PARN and the m7GpppG cap of mRNA plays a key role in stimulating the rate of deadenylation. Here we report the solution structures of the cap-binding domain of mouse PARN with and without the m7GpppG cap analog. The structure of the cap-binding domain adopts the RNA recognition motif (RRM) with a characteristic a-helical extension at its C-terminus, which covers the b-sheet surface (hereafter referred to as PARN RRM). In the complex structure of PARN RRM with the cap analog, the base of the N7-methyl guanosine (m7G) of the cap analog stacks with the solvent-exposed aromatic side chain of the distinctive tryptophan residue 468, located at the C-terminal end of the second b-strand. These unique structural features in PARN RRM reveal a novel cap-binding mode, which is distinct from the nucleotide recognition mode of the canonical RRM domains.
Poster presentation In pharmaceutical research and drug development, machine learning methods play an important role in virtual screening and ADME/Tox prediction. For the application of such methods, a formal measure of similarity between molecules is essential. Such a measure, in turn, depends on the underlying molecular representation. Input samples have traditionally been modeled as vectors. Consequently, molecules are represented to machine learning algorithms in a vectorized form using molecular descriptors. While this approach is straightforward, it has its shortcomings. Amongst others, the interpretation of the learned model can be difficult, e.g. when using fingerprints or hashing. Structured representations of the input constitute an alternative to vector based representations, a trend in machine learning over the last years. For molecules, there is a rich choice of such representations. Popular examples include the molecular graph, molecular shape and the electrostatic field. We have developed a molecular similarity measure defined directly on the (annotated) molecular graph, a long-standing established topological model for molecules. It is based on the concepts of optimal atom assignments and iterative graph similarity. In the latter, two atoms are considered similar if their neighbors are similar. This recursive definition leads to a non-linear system of equations. We show how to iteratively solve these equations and give bounds on the computational complexity of the procedure. Advantages of our similarity measure include interpretability (atoms of two molecules are assigned to each other, each pair with a score expressing local similarity; this can be visualized to show similar regions of two molecules and the degree of their similarity) and the possibility to introduce knowledge about the target where available. We retrospectively tested our similarity measure using support vector machines for virtual screening on several pharmaceutical and toxicological datasets, with encouraging results. Prospective studies are under way.