Conformational behaviour of C(alpha,alpha)-diphenylglycine: folded vs. extended structures in DphiG-containing tripeptides

BACKGROUND: Personality assessment may allow reliable measurement of risk of mood disorders. METHODS: A group of adults (804) representative of the general population were assessed by questionnaire. Personality types were measured by the Temperament and Character Inventory (TCI). RESULTS: Specific TCI configurations define personality types that can be described as hyperthymic, cyclothymic, irritable, and depressive. Each type had a unique profile of emotions, suicide attempts, and hospitalization. CONCLUSIONS: TCI traits are associated with mood disorders. LIMITATIONS: Different ways of measuring Kraepelinean subtypes may disagree. Whether differences in personality cause psychopathology, or vice versa, remains uncertain. CLINICAL RELEVANCE: Personality profiles help in assessing suicidality and planning treatment.     

Synthesis and conformational studies of peptides containing TOAC, a spin-labelled C alpha, alpha-disubstituted glycine

A variety of host L-alanine homo-peptides (to the pentamer) containing one or two spin-labelled TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) residues were synthesized by solution methods and fully characterized. The conformational features of the terminally blocked, doubly spin-labelled TOAC-(Ala)2-TOAC-Ala-pentapeptide were examined in the crystal state by X-ray diffraction and in solution using a combination of techniques (Fourier transform infrared, circular dichroism, cyclic voltammetry and electron spin resonance) in comparison with singly labelled shorter peptides. The 3(10)-helical structure of the pentapeptide, promoted by the two C alpha, alpha-disubstituted glycines under favourable experimental conditions, allows an interaction to take place between the two nitroxide TOAC side chains spaced by one turn of the helix. Taken together, these results suggest that TOAC is an excellent probe for exploring bends and helices in doubly labelled peptides.     

X-ray diffraction analysis of scrapie prion: intermediate and folded structures in a peptide containing two putative alpha-helices

Small proteinaceous infectious particles called prions cause certain neurodegenerative diseases in human and animals. Limited proteolysis of infectious scrapie prions PrP(Sc) yields an N-truncated polypeptide termed PrP 27-30, which encompasses residues 90 to 231 of PrP(Sc) and which assembles into 100 to 200 A wide amyloid rods. It has been hypothesized that the infectious prion is converted from its non-infectious cellular form (PrP(C)) by means of an alpha-helical to beta-sheet conformational change. Secondary structure analysis, computer modeling, and structural biophysics methods support this hypothesis. Residues 90 to 145 of PrP, which contain two putative alpha-helical domains H1 and H2, may be of particular relevance to the disease pathogenesis, as C-terminal truncation at residue 145 was found in a patient with an inherited prion disease. Moreover, our recent X-ray diffraction analysis suggests that the peptide consisting of these residues (designated SHa 90-145) closely models the amyloidogenic beta-sheet core of PrP. In the current study, we have analyzed in detail the X-ray diffraction patterns of SHa 90-145. Two samples were examined: one that was dehydrated under ambient conditions whilst in an external magnetic field (to induce fibril orientation), and another that was sealed after partial drying. The dried, magnetically oriented sample showed a cross-beta diffraction pattern in which the fiber axis (rotation axis) was parallel to the H-bonding direction of the beta-sheets. The major wide-angle peaks indicate the presence of approximately 40 A wide beta-crystallites, which constitute the protofilament. Each crystallite is composed of several orthogonal unit cells, normal to the fiber (a-axis) direction, having lattice constants a = 9.69 A, b = 6.54 A, and c = 18.06 A. Electron density maps were calculated by iterative Fourier synthesis using beta-silk as an initial phase model. The distribution of density indicated that there were two types of beta-sheet, suggesting that larger and smaller side-chains localized to different sheets. This would arise from folding of the polypeptide in which there are turns in the middle of both the H1 and H2 domains. A monoclinic macrolattice, with a = 9.61 A, b = c = 52.99 A and alpha = 114.6 degrees, was found to index all the reflections, including those in the low-angle region. This suggests that the beta-crystallites are nearly hexagonally packed. To account for the approximately 100 A wide fibers visualized by negative staining in the electron microscope, the beta-crystallites would be arranged in 4-mers. The partially dried sample showed a sharp 4.7 A reflection (from H-bonding) and five broad peaks superimposed on monotonically decreasing diffuse scattering. This solution-like scattering was modeled by an anisometric rectangle with a thickness comparable to a singe beta-chain. The structure, which occurred during dehydration, could be a transient in the alpha-helical to beta-sheet conversion, suggesting that formation of hydrogen bonding precedes the inter-sheet interaction and assembly into the amyloid of scrapie prion.     

Dual conformations of a T cell receptor V alpha homodimer: implications for variability in V alpha V beta domain association

The crystal structure of a mutant T cell receptor (TCR) V alpha domain containing a grafted third complementarity-determining region (CDR3) from a different V alpha was determined at 2.3 A resolution by molecular replacement using the wild-type V alpha structure as a search model. Like the wild-type V alpha domain, the mutant crystallized as a homodimer very similar to TCR V alpha V beta and antibody V(L)V(H) heterodimers, with the CDR loops disposed to form part of the antigen-binding site. However, the relative orientation of the two chains in the mutant V alpha homodimer differs from that in the wild-type by a rotation of 14 degrees such that the buried surface area in the dimer interface of the mutant is 140 A2 less than in the wild-type. While the residues forming the interface are essentially the same in the two structures, there are only four pairs of interface hydrogen bonds in the case of the mutant compared with eight for the wild-type. These results suggest that multiple relative orientations of the V alpha and V beta domains of TCRs may be possible, providing a significant contribution to TCR combining site diversity.     

Deformation induced alpha and epsilon martensites in Fe-Ni-Cr single crystals

The orientation dependence of an applied tensile stress on the formation of specific α martensite variants of the Kurdjumov-Sachs (K-S) orientation relationship in Fe-15Ni-15Cr single crystals are presented. Test temperatures were 185, 242 and 273 K,i.e., aboveM _s. Quantitative volume fraction measurements of deformation induceda ande martensite were made on crystals with the [100]γ, [1•10]γ, [•1•12]γ and [•2•13]γ tensile axes, α-martensite was only observed after 5 pct strain at 185K in all orientations, but the total volume fraction ofa martensite varied from <0.002 to 0.07 for the [100]γ and [•2•13]γ tensile axes respectively. The distribution of the K-S variants was also found to be sensitive to the direction of the applied stress, and 80 pet of the α martensite present in crystals oriented for easy glide had the same K-S variant. Epsilon martensite was found in all specimens but occurred only in the (111) planes which had slipped. Glen Stone, formerly graduate student, University of California at Berkeley     

Stimulating effect of pyroglutamylglutamylprolineamide, a prostatic, TRH-related tripeptide, on mouse sperm capacitation and fertilizing ability in vitro

The morbidity associated with total glossectomy for treatment of base of tongue carcinomas provides the impetus to investigate techniques to salvage the uninvolved normal anterior tongue. This report describes a method of reinnervation of the anterior tongue using a hypoglossal-lingual transfer. In Cynomolgus monkeys, unilateral transfers with and without a subsequent muscle fillet resulted in reinnervation from the base to the tip of the tongue. It is proposed that hypoglossal-lingual nerve transfers be considered to allow sparing and return of function to the anterior tongue in conjunction with a resection of the tongue base. Additional experiments confirmed that the base of the tongue, like other midline muscles, has bilateral and separate innervation. The presence of a physiological lingual-hypoglossal reflex in the normal animal was documented.     

Novel modified tripeptide inhibitors of alpha 4 beta 7 mediated lymphoid cell adhesion to MAdCAM-1

MAdCAM-1 specifically binds the lymphocyte integrin alpha 4 beta 7 and participates in the homing of leukocytes to intestinal mucosal sites. The LDT sequence located on the CD loop of MAdCAM-1 is an important binding site for MAdCAM-1/alpha 4 beta 7 interactions. N-Terminus acylation of the LDT motif and modification of the C-terminus carboxamide with amines led to low micromolar MAdCAM-1 inhibitors.     

Preparation and properties of polymeric colloidal crystals containing rare earth complexes

Rare earth organic complexes were introduced into the polymerization system, and the polymeric colloidal nanospheres containing rare earth complexes were prepared by emulsion copolymerization. The characterization results indicated that the polymeric spheres were small at nanometer size and the diameter was monodisperse, particularly the nanospheres possessed good fluorescent properties. Moreover, the polymeric nanospheres were self-assembled to fabricate the colloidal crystals, which were three-dimensional regular multilayer films. The polymeric colloidal crystal films exhibited excellent luminescent and novel optical properties.     

Predbaration and properties of polymeric colloidal crystals containing rare earth complexes

Rare earth organic complexes were introduced into the polymerization system, and the polymeric colloidal nanospheres containing rare earth complexes were prepared by emulsion copolymerization. The characterization results indicated that the polymeric spheres were small at nanometer size and the diameter was monodisperse, particularly the nanospheres possessed good fluorescent properties. Moreover, the polymeric nanospheres were self-assembled to fabricate the colloidal crystals, which were three-dimensional regular multilayer films. The polymeric colloidal crystal films exhibited excellent luminescent and novel optical properties.     

Structure-cytoprotective activity relationship of simple molecules containing an alpha,beta-unsaturated carbonyl system

In previous reports we attributed the cytoprotective activity of several sesquiterpene lactones to the presence of a nonhindered electrophilic acceptor in their structure. We suggested that the mechanism of protection would be, at least in part, mediated through a reaction between the electrophilic acceptor and the sulfhydryl-containing groups of the mucosa. We report here the gastric cytoprotective effect of simple molecules containing an alpha, beta-unsaturated carbonyl group. In the present paper, we undertake the study of molecular accessibility and molecular shape, in addition to conformational, electronic, and steric factors. Our results helped to establish two important facts connecting chemical structure with cytoprotective effect. Firstly, an adequate molecular accessibility appears to be necessary to produce the biological response, and secondly, the alpha,beta-unsaturated carbonyl system has to be included in a cyclic structure or, at least, in the proximity of a cyclic system.     

Detection of multiple conformations of the E-domain of 5S rRNA from Escherichia coli in solution and in crystals by NMR spectroscopy

NMR spectroscopy of the E-domain fragment of Escherichia coli 5S rRNA indicates that this molecule exists in solution as either a stem-loop or as a duplex with two U-U base pairs in the bulge region. At temperatures below 27 degrees C, interconversion between the monomeric and dimeric forms in solution occurs on a time scale of weeks and allows the preparation of samples on which NMR structure determinations can be carried out on predominantly monomeric or dimeric species. The NMR results obtained provide comparison data for the distinction between A- and B-form E.coli 5S rRNA and for the possible kinetics of conversion between these forms. NMR evidence is presented that the duplex form also exists in crystals and suggestions are made for means to obtain stem-loop conformations of E-domain and other small RNA stem-loop sequences in crystals.     

Effect of selective cytosine methylation and hydration on the conformations of DNA triple helices containing a TTTT loop structure by FT-IR spectroscopy

5-Methylcytosines have been introduced into triplex-forming-oligonucleotides and shown to extend the pH range over which a triplex forms with a homopurine-homopyrimidine tract of duplex DNA. As a host strand, an oligodeoxypyrimidine with a base sequence of 5'-d(TC)3T4(CT)3 ([CC]) was designed to form a hairpin triplex with a 5'-d-A(GA)2G ([AG6]) purine strand at acidic pH (Tsay, et al., (1995) J. Biomol. Str. Dyn., 13, 1235-1245). We here present results obtained by FT-IR spectroscopy concerning the conformation of the hairpin triplex as a function of the selective substitution of cytosines by 5-methylcytosines in the host strand. Namely, cytosines are substituted by 5-methylcytosines in either the 3'-pyrimidine portion ([CM]) or the 5'-pyrimidine portion ([MC]) or in both ([MM]) of the host strand. The acidic-induced transitions of the equimolar mixtures of the purine target with either of the four pyrimidine oligomers gives rise to different apparent pK values, i.e., [MM].[AG6] (6.2) > [MC].[AG6] (6.0) > [CM].[AG6] (5.7) > [CC].[AG6] (5.2) > single-stranded oligopyrimidines (4.6 +/- 0.2), indicating that cytosine methylation expands the pH range compatible with the hairpin triplex formation regardless of whether the substitution is in the 5'-pyrimidine (Hoogsteen) portion or in the 3'-pyrimidine (Watson-Crick) portion. Thermal denaturation profiles indicated that all the triplexes denatured in a monophasic manner in the pH range of 4.0 to 7.0, and that cytosine methylations in any position of the 16-base pyrimidine oligomer increase the stability of the hairpin triplex DNA. IR spectra recorded in D2O and H2O solutions revealed that cytosine methylation does not significantly influence the conformation of triplex DNA in solution, i.e., all the four triplexes accept a similar sugar conformation, and predominately take on a S-type sugar pucker with a relative proportion of two S-type sugars for one N-type. Furthermore, we also investigated the effect of relative humidity (RH) on the conformation of triplex MC.AG6 in hydrated films, and found that the conformational change induced by the decrease of RH, from predominant S-type to primary N-type sugar pucker, might first occur in the purine strand at 86% RH.