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At least 163 records · Page 9Linked to original sources
PubMed1984

A structural model of human erythrocyte band 2.1: alignment of chemical and functional domains.

Protein 2.1 is a 210-kilodalton protein that connects erythrocyte spectrin to the NH2-terminal cytoplasmic domain of band 3 and thereby functions as the essential linkage between the membrane skeleton and the bilayer. We cleaved this protein into specific chemical domains by limited digestion with trypsin and alpha-chymotrypsin at 0 degrees C. Intermediate-sized peptides were separated by two-dimensional isoelectric focusing/NaDodSO4/polyacrylamide gel electrophoresis and characterized by high resolution peptide mapping. We have established a provisional structural model of protein 2.1 by comparing the peptide maps of these chemical domains to maps obtained from larger overlapping chymotryptic fragments as well as fragments obtained from 2-nitro-5-thiocyanobenzoic acid cleavage. In addition to providing a provisional structural map of protein 2.1, we have identified two functional domains of protein 2.1, an 83-kilodalton tryptic peptide (T-83) which binds band 3 and a 65-kilodalton tryptic peptide (T-65) which binds spectrin. We have therefore localized the functional domains along our linear map of protein 2.1.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1990

How wide is the widening scope of psychoanalysis and how solid is its structural model? Some concerns and observations.

The author advances the thesis that in the past 35 years there has been a relatively silent but nonetheless significant movement within the mainstream of American psychoanalysis toward a more "modest" position. This movement has been stimulated from different sources, sometimes with diverse goals and different programs. One determinant was the reaction to the post-World War II euphoria in regard to psychoanalysis and its possible therapeutic powers. Another element has been the ongoing consolidation of our knowledge and understanding of the ego-psychological, structural-model approach to analytic theory and technique, an approach which emphasizes both intrapsychic conflict and compromise formations. A consequence of this more modest position has been a greater appreciation of the limitations of psychoanalysis as well as the significance of those limitations. This more realistic appraisal of psychoanalysis may not have encouraged the widening scope of the indications for analysis, but the enhanced understanding of its limitations offers the promise of more effective psychoanalytic work in areas that have not been considered ideal for the so-called "traditional" analysis. It is suggested that more sophisticated approaches in the analysis of resistance and character, of "conflict" (in distinction to "diagnoses"), together with a more applicable understanding of the psychoanalytic process, can all contribute to a deepening, if not necessarily widening, of our psychoanalytic endeavors.

Humans↗
PubMed1992

Structure model of core proteins in photosystem I inferred from the comparison with those in photosystem II and bacteria; an application of principal component analysis to detect the similar regions between distantly related families of proteins.

A principal component analysis based on the physico-chemical properties of amino acid residues is developed to assign similar regions between distantly related families of proteins, taking account of the species diversities in respective families. The most important advantage of this analysis should be that it reflects different physico-chemical properties and thus can predict more detailed structural properties, including the transmembrane helices, than the hydropathy analysis. Its first application reconfirms the similarity between the core proteins of photosynthetic reaction center in purple bacteria and those of photosystem II, indicating that the low percentage of identical amino acid residues estimated previously between them is due to much allowance for amino acid substitutions in purple bacteria. The application of this analysis to the core proteins of photosystem I reveals that any of these proteins includes two domains, each showing high similarity to the amino acid sequences of core proteins in photosystem II and purple bacteria. A core structure model of A1 and A2 proteins folded into four layers of sheets of transmembrane helices is proposed to provide a molecular basis for the electron pathway suggested by spectroscopic experiments as well as for the interaction sites with plastocyanin, 9 kDa protein and LHC proteins.

Amino Acid Sequence↗
PubMed1993

A structural model for the GroEL chaperonin.

Individual particle analysis of end views from negatively stained specimens of purified GroEL from Escherichia coli showed the presence of two different particle populations, those with a six-fold symmetry and those with a seven-fold symmetry, when studied at pH 7.7 and 5.0. Image processing of particles from frozen-hydrated specimens revealed at both pH values a homogeneous population of particles with a strong seven-fold symmetry component and an average image with seven asymmetric units. Biochemical analysis of purified GroEL showed unequivocally the presence of a single polypeptide with the N-terminal sequence identical to that of GroEL. These results are compatible with a structural model of GroEL as an asymmetric aggregate built up by two rings of seven-fold and six-fold symmetries, respectively.

Amino Acid Sequence↗
PubMed1987

Drosophila mitochondrial DNA: conserved sequences in the A + T-rich region and supporting evidence for a secondary structure model of the small ribosomal RNA.

The sequence of a segment of the Drosophila virilis mitochondrial DNA (mtDNA) molecule that contains the A + T-rich region, the small rRNA gene, the tRNA(f-met), tRNA(gln), and tRNA(ile) genes, and portions of the ND2 and tRNA(val) genes is presented and compared with the corresponding segment of the D. yakuba mtDNA molecule. The A + T-rich regions of D. virilis and D. yakuba contain two correspondingly located sequences of 49 and 276/274 nucleotides that appear to have been conserved during evolution. In each species the replication origin of the mtDNA molecule is calculated to lie within a region that overlaps the larger conserved sequence, and within this overlap is found a potential hairpin structure. Substitutions between the larger conserved sequences of the A + T-rich regions, the small mt-rRNA genes, and the ND2 genes are biased in favor of transversions, 71-97% of which are A----T changes. There is a 13.8 times higher frequency of nucleotide differences between the 5' halves than between the 3' halves of the D. virilis and D. yakuba small mt-rRNA genes. Considerations of the effects of observed substitutions and deletion/insertions on possible nucleotide pairing within the small mt-rRNA genes of D. virilis and D. yakuba strongly support the secondary structure model for the Drosophila small mt-rRNA that we previously proposed.

Adenine↗
PubMed1982

A structural model of 5S RNA from E. coli based on intramolecular crosslinking evidence.

We describe new results obtained using the bifunctional chemical reagent phenyldiglyoxal (PDG) to study the intramolecular crosslinking of ribosomal 5S RNA from E. coli. In a previous publication (Wagner & Garrett [1]) we reported the identification of a crosslink in the stem region of 5S RNA (G2-G112) using the same reagent but were unable to obtain further information because of the presence of monofunctional adducts which confused the analyses. To overcome this problem, we have removed the monoaddition products by coupling them via their free reagent ends to a solid support bearing reactive groups. Using this system we have been able to identify a new crosslink G41-G72 in native 5S RNA which has considerable structural implications. We propose a structural model in which the proximity of both nucleotides is maintained by secondary interactions.

Base Sequence↗
PubMed1985

Model structure for the inflammatory protein C5a.

The complement cleavage product C5a is a potent stimulant of inflammatory processes; thus, inhibition of C5a activity is of therapeutic interest. The three-dimensional structure of the major portion of C5a was modeled from the homologous C3a crystal structure by comparative modeling techniques. The model shows that core residues of C5a are completely conserved, while external residues differ from C3a. Even though the amino-terminal 12 residues of C3a are disordered in the crystal, this sequence in C5a may form an amphipathic helix. The distribution of species sequence differences in the complete C5a structure suggests a possible receptor binding site.

Amino Acid Sequence↗
PubMed1988

Purification, sequence, and model structure of charybdotoxin, a potent selective inhibitor of calcium-activated potassium channels.

Charybdotoxin (ChTX), a protein present in the venom of the scorpion Leiurus quinquestriatus var. hebraeus, has been purified to homogeneity by a combination of ion-exchange and reversed-phase chromatography. Polyacrylamide gel electrophoresis, amino acid analysis, and complete amino acid sequence determination of the pure protein reveal that it consists of a single polypeptide chain of 4.3 kDa. Purified ChTX is a potent and selective inhibitor of the approximately 220-pS Ca2+-activated K+ channel present in GH3 anterior pituitary cells and primary bovine aortic smooth muscle cells. The toxin reversibly blocks channel activity by interacting at the external pore of the channel protein with an apparent Kd of 2.1 nM. The primary structure of ChTX is similar to a number of neurotoxins of diverse origin, which suggests that ChTX is a member of a superfamily of proteins that modify ion-channel activities. On the basis of this similarity, the three-dimensional structure of ChTX has been modeled from the known crystal structure of alpha-bungarotoxin. These studies indicate that ChTX is useful as a probe of Ca2+-activated K+-channel function and suggest that the proposed tertiary structure of ChTX may provide insight into the mechanism of channel block.

Amino Acid Sequence↗
PubMed1983

Refined secondary structure models for the 16S and 23S ribosomal RNA of Escherichia coli.

The complete range of published sequences for ribosomal RNA (or rDNA), totalling well over 50,000 bases, has been used to derive refined models for the secondary structures of both 16S and 23S RNA from E. coli. Particular attention has been paid to resolving the differences between the various published secondary structures for these molecules. The structures are described in terms of 133 helical regions (45 for 16S RNA and 88 for 23S RNA). Of these, approximately 20 are still tentative or unconfirmed. A further 20 represent helical regions which definitely exist, but where the detailed base-pairing is still open to discussion. Over 90 of the helical regions are however now precisely established, at least to within one or two base pairs.

Animals↗
PubMed1995

Structural models of Na+, Ca2+, and K+ channels.

The structure determination of voltage-gated channels by the combination of molecular modeling and mutagenesis experiments is a long term, iterative process. As such, the models should be considered as a work in progress, with changes expected as more data becomes available. The primary role of the models is that they assimilate the known data and provide ideas for further experiments to elucidate the real structures. Although the models presented here have already gone through two or three cycles of development and testing, many aspects remain tentative. Perhaps the most significant result so far is that the P segment was experimentally confirmed to form the ion-selective part of the channel. In a subsequent cycle of testing and modeling, the specific residues responsibility for Na+ and Ca2+ selectivity have been identified and the selectivity filter of K+ channels is now predicted to be formed by the side chains, but rather by the carbonyl oxygens of the conserved Gly-Tyr-Gly sequence backbone. As another example, the 9p residue of the P segment of K+ channels was originally modeled as either being buried in the protein or accessible channels was originally modeled as either being buried in the protein or accessible from inside the cell only. However, once mutation of this residue to histidine was found to affect blockade by extracellular TEA, protons, Zn2+ and histidine reagents (DeBiasi et al., 1993), the models were updated to have this and the hydrophilic residues in the first part of P form a helix that comprises part of the extracellular, outer vestibular of the pore. While this motif was used also for Na+ and Ca2+ pore models (see Fig. 2) where the putative helices are amphipathic, it remains to be verified. Modeling of the size and shape of the outer vestibule of K+ channels was also aided by the data for the binding of CTX in the extracellular entrance to the pore. Similarly, experiments with peptide toxins such as mu and omega conotoxins may prove useful in modeling the outer vestibules of the Na+ and/or Ca2+ channels. While important advances have been made, it is important to realize that these approaches are still very new. In the future we are likely to see improvements on both the theoretical and experimental sides which will greatly advance the process.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Molecular genetics of the VDAC ion channel: structural model and sequence analysis.

The voltage-dependent anion-selective channel of the outer mitochondrial membrane provides a unique system in which to study the molecular basis of voltage gating of ion flow. We have cloned and sequenced a cDNA coding for this protein in yeast. From the derived amino acid sequence, we have generated a preliminary model for the secondary structure of the protein which suggests that the protein forms a "beta-barrel" type structure. Comparison of the VDAC amino acid sequence with that of the bacterial porins has indicated that the two classes of molecules appear to be unrelated.

Amino Acid Sequence↗
PubMed1991

An initial slope method for model structure: independent estimation of the elimination rate constant of a metabolite.

A model structure-independent method for calculating the true elimination rate constant of a primary metabolite is presented. It does not require direct metabolite administration and uses data on drug and metabolite blood (plasma) concentrations after a bolus drug input. The method has been tested and compared with the moment method and the area function method using errorless and errant data simulated on the basis of one- and two-compartment models of the metabolite kinetics. In contrast to known methods the proposed method provided exact estimates of the elimination rate constant in the case of errorless data of both one- and two-compartment models. However the estimates are sensitive to random errors in the concentration data.

Mathematical Computing↗
PubMed1991

Structured model for cell growth and enzyme production by recombinant Escherichia coli.

A structured cell model has been developed to describe the cultivation of recombinant Escherichia coli K12 with multicopy plasmid under the control of a lambda PR-promoter and a temperature-sensitive lambda cI 857 repressor. The model, based on measurements of a batch culture in a stirred tank reactor, allows statements to be made on the time variation of intracellular processes. Based on cell regulation, the substrate transfer into the cell was considered to be the rate-limiting step for substrate utilization. The model describes substrate utilization, cell growth, and product formation by means of a system of time-dependent, coupled, and partly non-linear differential equations. The solution of these equations allows calculation of the time variation of the concentrations of substrates (glucose and amino acids), dissolved oxygen and cells in the broth as a function of time and the process parameters.

Cell Division↗
PubMed1976

Structural model of vestibular effects on the blood pressure.

The model described in the present work is a structural presentation of certain aspcets of the vesibular effects on the blood pressure. The model comprises the joint action of the otolith system and the semicircular canals, gangl. Scarpe, the vestibular nuclei, the vasomotor centre and the nuclei of n. vagus. The direct transfer of information both from gangl. Scarpe to the vasoregulating centre and from nucl. Schwalbe to the vagal nuclei, as well as its polysynaptic transmission, are considered. The model examines a case when only two factors, namely decrease in the heart rate controlled by n. vagus and decrease in the heart tone controlled by the vasoregulating centre, determine the effect of blood pressure drop after vestibular stimulation. The structure of the model is flexible and permits its elaboration by including additional factors for the blood pressure drop.

Blood Pressure↗
PubMed1986

Polydepsipeptides. 13. Synthesis and 1H-n.m.r. analysis of collagen model structures.

The synthesis of three collagen model analogs is described: Ac-Ala-Gly-Pro-Ala-Gly-Pro-NHMe, Ac-Ala-Gly-Pro-Ala-Glc-Pro-NHMe, and Ac-Ala-Glc-Pro-Ala-Gly-Pro-NHMe, where Glc stands for glycolic acid. The 1H-n.m.r. properties of these compounds in dimethylsulfoxide-d6 and trifluoroethanol are described. While in DMSO-d6 the compounds are random, in TFE the glycine amide protons seem to be less solvent exposed than the other amide protons. Little difference was found in the behavior of the three compounds.

Amino Acid Sequence↗
PubMed1994

Molecular dynamics studies on peroxidases: a structural model for horseradish peroxidase and a substrate adduct.

Molecular dynamics (MD) calculations are performed on cytochrome c peroxidase (CcP) and on horseradish peroxidase, isoenzyme C (HRP), and its substrate adduct with p-cresol. For CcP, a refinement in solution of the X-ray structure is obtained which indicates that in solution the protein structure is very similar to that in the crystal. For HRP, the X-ray structure is not available. We have generated a model of this protein based on the recently reported structure of the similar lignin peroxidase (LiP) protein. This model involves the entire system as all the amino acid residues match the sequence. This HRP model was refined through energy minimization and MD calculations. A refined structural model for HRP, for the first time involving the entire protein, is therefore now available. The tertiary structure of HRP is close to that of LiP, and also the active site in the two proteins has significantly similar structures. The well-ordered water molecules and the extensive H-bond network present in the X-ray structure of CcP is maintained in the dynamics without any constraints, indicating that the active site residues produce a field strong enough to make all these interactions quite stable. Interestingly, also in HRP a network of ordered water molecules and H-bonds is present, again without constraints. This is consistent with the similarities of the active sites in the two proteins. Finally, we have calculated the MD structure of the adduct of HRP and a substrate molecule, p-cresol. This structural model is compared with the NMR data, which are in fairly good agreement. The binding site and the protein-substrate interactions are discussed.

Binding Sites↗
PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗
PubMed1977

[Small-angle X-ray-scattering investigation and structural-model study of the fatty-acid synthetase from pig liver (author's transl)].

The structure of the fatty acid synthetase from pig liver was studied on models based upon structural and functional properties selected from pertinent results available from numerous investigations carried out with fatty acid synthetases from this and other sources. When comparing small-angle X-ray-scattering curves calculated with these models and curves obtained from small-angle X-ray-scattering experiments carried out with the pig-liver enzyme, we tried to select a model which would lead to an acceptable correlation between the calculated and the experimental curves and at the same time fulfil the known structural and functional requirements. The comparison of the curves was started with a model of low complexity. The observed discrepancy, together with arguments from the structural and the functional properties, helped decide which is the next most reasonable model to be considered. This procedure was repeated for five models of increasing complexity. In the model which led to the best fit the multienzyme complex is composed of two halves in an assymetric conformation including hollow spaces. This highly anisotropic model would imply that the two halves change their conformation each time a synthetic cycle is completed and that the growing fatty acid is handed over from one half to the other.

Animals↗