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PubMed1993

Unique secondary and tertiary structural features of the eucaryotic selenocysteine tRNA(Sec).

Cotranslational insertion of selenocysteine into selenoenzymes is mediated by a specialized transfer RNA, the tRNA(Sec). We have carried out the determination of the solution structure of the eucaryotic tRNA(Sec). Based on the enzymatic and chemical probing approach, we show that the secondary structure bears a few unprecedented features like a 9 bp aminoacid-, a 4 bp thymine- and a 6 bp dihydrouridine-stems. Surprisingly, the eighth nucleotide, although being a uridine, is base-paired and cannot therefore correspond to the single-stranded invariant U8 found in all tRNAs. Rather, experimental evidence led us to propose that the role of the invariant U8 is actually played by the tenth nucleotide which is an A, numbered A8 to indicate this fact. The experimental data therefore demonstrate that the cloverleaf structure we derived experimentally resembles the hand-folded model proposed by Böck et al (ref. 3). Using the solution data and computer modelling, we derived a three-dimensional structure model which shows some unique aspects. Basically, A8, A14, U21 form a novel type of tertiary interaction in which A8 interacts with the Hoogsteen sites of A14 which itself forms a Watson-Crick pair with U21. No coherent model containing the canonical 15-48 interaction could be derived. Thus, the number of tertiary interactions appear to be limited, leading to an uncoupling of the variable stem from the rest of the molecule.

Animals↗

PubMed1998

Structural features impose tight peptide binding specificity in the nonclassical MHC molecule HLA-E.

The crystal structure of the nonclassical human class lb MHC molecule HLA-E has been determined in complex with a prototypic ligand, the nonamer peptide (VMAPRTVLL), derived from the highly conserved residues 3-11 of the human MHC class la leader sequence. The mode of peptide binding retains some of the standard features observed in MHC class la complexes, but novel features imply that HLA-E has evolved to mediate specific binding to a tightly defined set of almost identical hydrophobic peptides from the highly conserved class l leader sequences. These molecular adaptations make HLA-E a rigorous checkpoint at the cell surface reporting on the integrity of the antigen processing pathway to CD94/NKG2 receptor-bearing natural killer cells.

Crystallography↗

PubMed2001

Conjugative plasmid protein TrwB, an integral membrane type IV secretion system coupling protein. Detailed structural features and mapping of the active site cleft.

Bacterial conjugation is an example of macromolecular trafficking between cells and responsible for the spreading of antibiotic resistance among bacteria. It involves translocation of single-stranded DNA across membranes through a type IV secretion system. A coupling protein links the DNA-processing nucleoprotein complex, the relaxosome, with the transport apparatus during cell mating. In Escherichia coli plasmid R388 such a protein is TrwB, a basic integral inner-membrane nucleoside-triphosphate-binding protein. TrwB is the structural prototype for the type IV secretion system coupling proteins, a family of proteins essential for macromolecular transport between cells and export. The structure of a soluble TrwB variant unveils an elongated molecule with six equivalent protein units featuring a spherical quaternary structure, leaving a central channel. The structures of the non-liganded protein and four different complexes with substrate analogues and products allow the precise description of the active site architecture. The active sites are located at the interface between protomers, each of them shaped mainly by residues of one monomer, but including two crucial arginine residues belonging to the adjacent molecule. Upon substrate binding and putative hydrolysis, conformational changes are transferred from the external surface to the interior central channel.

Anions↗

PubMed1999

Responses of auditory-cortex neurons to structural features of natural sounds.

Sound-processing strategies that use the highly non-random structure of natural sounds may confer evolutionary advantage to many species. Auditory processing of natural sounds has been studied almost exclusively in the context of species-specific vocalizations, although these form only a small part of the acoustic biotope. To study the relationships between properties of natural soundscapes and neuronal processing mechanisms in the auditory system, we analysed sound from a range of different environments. Here we show that for many non-animal sounds and background mixtures of animal sounds, energy in different frequency bands is coherently modulated. Co-modulation of different frequency bands in background noise facilitates the detection of tones in noise by humans, a phenomenon known as co-modulation masking release (CMR). We show that co-modulation also improves the ability of auditory-cortex neurons to detect tones in noise, and we propose that this property of auditory neurons may underlie behavioural CMR. This correspondence may represent an adaptation of the auditory system for the use of an attribute of natural sounds to facilitate real-world processing tasks.

Animals↗

PubMed1993

Assessment of disparate structural features in three models of the hepatitis delta virus ribozyme.

Three models for the secondary structure of the hepatitis delta virus (HDV) antigenomic self-cleaving RNA element were tested by site-directed mutagenesis. Two models in which bases 5' to the cleavage site are paired with sequence at the 3' end of the element were both inconsistent with the data from the mutagenesis. Specifically, mutations in the 3' sequence which decrease self-cleavage activity could not be compensated by base changes in the 5' sequence as predicted by these models. The evidence was consistent with a third model in which the 3' end pairs with a portion of a loop within the ribozyme sequence to generate a pseudoknot structure. This same pairing was also required to generate higher rates of cleavage in trans with a 15-mer ribozyme, thus ruling out a proposed hammerhead-like 'axehead' model for the HDV ribozyme.

Base Sequence↗

PubMed2003

Organization and dynamics of tryptophan residues in erythroid spectrin: novel structural features of denatured spectrin revealed by the wavelength-selective fluorescence approach.

We have investigated the organization and dynamics of the functionally important tryptophan residues of erythroid spectrin in native and denatured conditions utilizing the wavelength-selective fluorescence approach. We observed a red edge excitation shift (REES) of 4 nm for the tryptophans in the case of spectrin in its native state. This indicates that tryptophans in spectrin are localized in a microenvironment of restricted mobility, and that the regions surrounding the spectrin tryptophans offer considerable restriction to the reorientational motion of the water dipoles around the excited state tryptophans. Interestingly, spectrin exhibits a REES of 3 nm even when denatured in 8 M urea. This represents the first report of a denatured protein displaying REES. Observation of REES in the denatured state implies that some of the structural and dynamic features of this microenvironment around the spectrin tryptophans are retained even when the protein is denatured. Fluorescence quenching data of denatured spectrin support this conclusion. In addition, we have deduced the organization and dynamics of the hydrophobic binding site of the polarity-sensitive fluorescent probe PRODAN that binds erythroid spectrin with high affinity. When bound to spectrin, PRODAN exhibits a REES of 9 nm. Because PRODAN binds to a hydrophobic site in spectrin, such a result would directly imply that this region of spectrin offers considerable restriction to the reorientational motion of the solvent dipoles around the excited state fluorophore. The results of our study could provide vital insight into the role of tryptophans in the stability and folding of spectrin.

Animals↗

PubMed1992

Interaction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes.

Circular dichroism and fluorescence spectroscopy were used to investigate the structure of the p85 alpha subunit of the PI 3-kinase, a closely related p85 beta protein, and a recombinant SH2 domain-containing fragment of p85 alpha. Significant spectral changes, indicative of a conformational change, were observed on formation of a complex with a 17 residue peptide containing a phosphorylated tyrosine residue. The sequence of this peptide is identical to the sequence surrounding Tyr751 in the kinase-insert region of the platelet-derived growth factor beta-receptor (beta PDGFR). The rotational correlation times measured by fluorescence anisotropy decay indicated that phosphopeptide binding changed the shape of the SH2 domain-containing fragment. The CD and fluorescence spectroscopy data support the secondary structure prediction based on sequence analysis and provide evidence for flexible linker regions between the various domains of the p85 proteins. The significance of these results for SH2 domain-containing proteins is discussed.

Amino Acid Sequence↗

PubMed2005

On the structural features of hairpin triloops in rRNA: from nucleotide to global conformational change upon ligand binding.

RNA structure can be viewed as both a construct composed of various structural motifs and a flexible polymer that is substantially influenced by its environment. In this light, the present paper represents an attempt to reconcile the two standpoints. By using the 3D structures both of four (16S and 23S) portions of unbound 50S, H50S, and T30S ribosomal subunits and of 38 large ribonucleoligand complexes as the starting point, the behavior, which is induced by ligand binding, of 73 hairpin triloops with closing g-c and c-g base pairs was investigated using root-mean-square deviation (RMSD) approach and pseudotorsional (eta,theta) convention at the nucleotide-by-nucleotide level. Triloops were annotated in accordance with a recent proposal of geometric nomenclature. A simple measure for the determination of the strain of a triloop is introduced. It is believed that a possible classification of the interior triloops, based on the 2D eta-theta unique path, will aid to conceive their local behavior upon ligand binding. All rRNA residues in contact with ligands as well as regions of considerable conformational changes upon complex formation were identified. The analysis offers the answer to: how proximal to and how far from the actual ligand-binding sites the structural changes occur?

Base Sequence↗

PubMed1997

Sequence and structural features of plant and fungal tyrosinases.

Tyrosinases from various organisms are compared with respect to enzymatic structure, primary, secondary and tertiary structure, domain structure, Cu binding sites, maturation mechanism and activation mechanism. On the basis of these comparisons, and by using hemocyanin structure as a template, a structure model for the active site of tyrosinases is proposed.

Amino Acid Sequence↗

PubMed2000

Structural features of MHC class I molecules that might facilitate alternative pathways of presentation.

Comparisons of the structures of different mouse MHC class I molecules define how polymorphic residues determine the unique structural motif and atomic anchoring of their bound peptides. Here, Ted Hansen and colleagues speculate that quantitative differences in how class I molecules interact with peptide, beta2-microglobulin and molecular chaperones that facilitate peptide loading might determine their relative participation in different pathways of antigen presentation.

Animals↗

PubMed1987

Antigelling and antisickling bisphenyl oligopeptides and peptide analogues have similar structural features.

Single-crystal X-ray diffraction was used to determine the three-dimensional structures of two antigelling oligopeptides, L-lysyl-L-phenylalanyl-L-phenylalanine and L-phenylalanylglycylglycyl-D-phenylalanine, and two antisickling peptide analogues, L-phenylalanine benzyl ester and N-phenylacetyl-L-phenylalanine. Although these bisphenyl compounds are chemically quite different from one another, they demonstrate unusual structural similarities: The molecules have compact conformations in which the two phenyl rings are positioned approximately 5 A apart with interplanar angles approaching 90 degrees, thereby making intramolecular edge-to-face interactions. In addition, the polar atoms, nitrogen and oxygen, are in close proximity without forming intramolecular hydrogen bonds. The relative spatial distribution of polar and nonpolar atoms renders the structures compact and amphipathic. The intramolecular edge-to-face interaction between two aromatic rings, which brings a hydrogen atom with relative positive charge near the pi-electron cloud with relative negative charge, is enthalpically favorable and maintains the molecules in a compact and amphipathic conformation. Nonbonded potential energy calculations were used to characterize the energetics of the aromatic-aromatic interaction, and they showed that the observed geometry is stabilized enthalpically by a favorable interaction on the order of -1 to -2 kcal/mol. Structural differences between the two antisickling and the two antigelling agents suggest that molecular volume limits red cell membrane passage. These data provide a molecular structural framework from which to design and synthesize amphipathic bisphenyl compounds that both bind to deoxy sickle cell hemoglobin and cross the erythrocyte membrane.

Antisickling Agents↗

PubMed1991

New structural features of the flagellar base in Salmonella typhimurium revealed by rapid-freeze electron microscopy.

The structure of the flagellar base in Salmonella typhimurium has been studied by rapid-freeze techniques. Freeze-substituted thin sections and freeze-etched replicas of cell envelope preparations have provided complementary information about the flagellar base. The flagellar base has a bell-shaped extension reaching as far as 50 nm into the bacterial cytoplasm. This structure can be recognized in intact bacteria but was studied in detail in cell envelopes, where some flagella lacking parts of the bell were helpful in understanding its substructure. Structural relationships may be inferred between this cytoplasmic component of the flagellum and the recently described flagellar intramembrane particle rings as well as the structures associated with the basal body in isolated, chemically fixed flagella.

Flagella↗

PubMed1997

[Structural features of the modified BARE-retroelement in the barley (Hordeum vulgare L.) genome].

The primary structure of the 4.2-kb BamHI-fragment occurring abundantly in the genome of barley Hordeum vulgare was determined. By means of computer analysis, considerable homology was found between this fragment and the copia-like BARE-l retrotransposon studied earlier. A unique distinction of the BamHI fragment is its symmetrical structure caused by the presence of two mutually inverted parts, each of which is homologous to a long region of BARE-l including a 5'-LTR (long terminal repeat) and the adjacent leader sequence. No sequences homologous to the coding domains of BARE-l were revealed in the fragment. However, potentially functional signals were found: TATA boxes and primer-binding sites (PBS) exhibiting statistically significant homology to the corresponding regulatory signals of known retroelements. Thus, we have revealed and characterized a repeated element of the H. vulgare genome that is a markedly modified derivative of the BARE family of retrotransposons of this genome.

Base Sequence↗

PubMed1998

Structural features of the aldose reductase and aldehyde reductase inhibitor-binding sites.

The three-dimensional structures of aldose reductase and aldehyde reductase, members of the aldo-keto reductase superfamily, are composed of similar alpha/beta TIM-barrels. However, examination of the structures reveals that the inhibitor-binding site of aldose reductase differs from that of aldehyde reductase due to the participation of non-conserved residues in its formation. This information will be useful in the design of inhibitors to prevent or delay diabetic retinopathy. A review of the structures of the inhibitor-binding sites is presented.

Aldehyde Reductase↗

PubMed2006

Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations.

The rational development of specific inhibitors for the approximately 500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors.

Adenosine Triphosphate↗

PubMed2002

Functional mapping of the rat olfactory bulb using diverse odorants reveals modular responses to functional groups and hydrocarbon structural features.

In an effort to understand the olfactory code of rats, we collected more than 1,500,000 measurements of glomerular activity in response to 54 odorants selected to provide differences in functional groups and hydrocarbon structure. Each odorant evoked a unique response pattern by differentially stimulating clusters of glomeruli, called modules. Odorants sharing specific aspects of their structure activated the same modules, allowing us to relate responses to structure across approximately 80% of the glomerular layer. The most obvious relationship was between the presence of particular oxygen-containing functional groups and the activity of glomeruli within dorsal modules. Functional group-specific responses were observed for odorants possessing a wide range of hydrocarbon structure, including aliphatic, cyclic, and aromatic features. Even formic acid and acetone, the simplest odorants possessing acid or ketone functional groups, respectively, stimulated modules specific for these functional groups. At the same time, quantitative analysis of pattern similarities revealed relationships in activation patterns between odorants of similar hydrocarbon structure. The odorant responses were reliable enough to allow us to predict accurately specific aspects of odorant molecular structure from the evoked glomerular activity pattern, as well as predicting the location of glomerular activity evoked by novel odorants.

Administration, Inhalation↗

PubMed1999

Revision of the functional analysis and structural features of immortalized dendritic cell lines derived from mice lacking both type I and type II interferon receptors.

Cell lines with dendritic morphology were obtained from several organs of mice lacking both type I and II interferon receptors after a retroviral immortalization procedure. Their surface antigen phenotype was analyzed by flow cytometry with monoclonal antibodies and their functional capabilities to induce antigen dependent specific immune response was also determined. Two representative cell lines called AG101 (skin-derived) and AG116 (brain-derived) were cloned and analyzed in more detail. Cytometric analysis showed that they constitutively expressed the cell surface markers CD45, CD1 1b, MHC class II, F4/80, N418, B7-2 and ICAM1. Despite both cell lines expressing Thy-1 only, the AG116 show CD4 but both were negative for CD8 and B220. The functional analysis showed that the cell lines were capable and very efficient at actively taking up, processing and presenting soluble antigens like Ovalbumin (OVA). The processed protein was presented by both cell lines to the OVA-peptide-specific T cell hybridoma BO97.105, which responded specifically with the production of IL-2. In addition AG101 and AG116 cells were able to induce in naive allogeneic T cells, a mixed lymphocyte reaction, determined by T cell proliferation and T cell dependent L-2 production. Moreover, the capability to prime naive syngeneic T cells was also demonstrated by loading AG101 and AG116 cells with soluble antigens, then co-culturing with naive T cells which yielded both T cell proliferation and IL-2 production. The cell lines priming capability was shown to be quite similar, as freshly isolated and cultured cutaneous dendritic cells from 129Sv/Lv mice (wtDCs) to prime naive T cells. In addition to a basal production of IL-6, the cell lines were found to increase their synthesis of IL-6 and IL-12 p40 after interaction with T cells in a similar way as mature wtDCs. Also it was determined that DC cell lines devoid of functional IFN system allow the replication of infectious agents like BDV and even are able to induce in vivo a specific humoral response against proteins of the BDV. Therefore, the cell lines AG101 and AG116 show structural and functional features of DCs. They are able to take up, process and present antigens as well as prime naive T cell in a similar manner as nontransformed DC. Therefore, these cell lines will be useful for studying the interactions between DC and the effectors cells of the immune response at the clonal level and in the absence of functional interferon receptors.

Animals↗

PubMed2002

Epithelial barrier function: assembly and structural features of the cornified cell envelope.

Terminally differentiating stratified squamous epithelial cells assemble a specialized protective barrier structure on their periphery termed the cornified cell envelope (CE). It is composed of numerous structural proteins that become cross-linked by several transglutaminase enzymes into an insoluble macromolecular assembly. Several proteins are involved in the initial stages of CE assembly, but only certain proteins from a choice of more than 20 different proteins are used in the final stages of CE reinforcement, apparently to meet tissue-specific requirements. In addition, a variable selection of proteins may be upregulated in response to genetic defects of one of the CE proteins or tissue injury, in an effort to maintain an effective barrier. Additionally, in the epidermis and hair fiber cuticle, a layer of lipids is covalently attached to the proteins, which provides essential water barrier properties. Here we describe our current understanding of CE structure, a possible mechanism of its assembly, and various disorders that cause a defective barrier.

Animals↗