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At least 433 records · Page 24Linked to original sources
PubMed1997

Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with cyclic urea inhibitors.

In cell cultures, the key residues associated with HIV-1 resistance to cyclic urea-based HIV-1 protease (PR) inhibitors are Val82 and Ile84 of HIV-1 PR. To gain an understanding of how these two residues modulate inhibitor binding, we have measured the Ki values of three recombinant mutant proteases, I84V, V82F, and V82F/I84V, for DMP323 and DMP450, and determined the three-dimensional structures of their complexes to 2.1-1.9 A resolution with R factors of 18.7-19.6%. The Ki values of these mutants increased by 25-, 0.5-, and 1000-fold compared to the wild-type values of 0.8 and 0.4 nM for DMP323 and DMP450, respectively. The wild-type and mutant complexes overall are very similar (rms deviations of 0.2-0.3 A) except for differences in the patterns of their van der Waals (vdw) interactions, which appear to modulate the Ki values of the mutants. The loss of the CD1 atom of Ile84, in the I84V mutant complexes, creates a hole in the S1 subsite, reducing the number of vdw contacts and increasing the Ki values. The V82F mutant binds DMP323 more tightly than wild type because the side chain of Phe82 forms additional vdw and edge-to-face interactions with the P1 group of DMP323. The Ki values of the single mutants are not additive because the side chain of Phe82 rotates out of the S1 subsite in the double mutant (the chi 1 angles of Phe82 and -182 in the V82F and V82F/I84V mutants differ by 90 and 185 degrees, respectively), further reducing the vdw interactions. Finally, compensatory shifts in the I84V and V82F/ I84V complexes pick up a small number of new contacts, but too few to offset the initial loss of interactions caused by the mutations. Therefore, our data suggest that variants persist in the presence of DMP323 and DMP450 because of a decrease in vdw interactions between the mutant proteases and inhibitors.

Azepines↗
PubMed2001

Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors.

We have previously reported on the unexpected flipped conformation in the cyclic sulfamide class of inhibitors. An attempt to induce a symmetric binding conformation by introducing P2/P2' substituents foreseen to bind preferentially in the S2/S2' subsite was unsuccessful. On the basis of the flipped conformation we anticipated that nonsymmetric sulfamide inhibitors, with P2/P2' side chains modified individually for the S1' and S2 subsites, should be more potent than the corresponding symmetric analogues. To test this hypothesis, a set of 18 cyclic sulfamide inhibitors (11 nonsymmetric and 7 symmetric) with different P2/P2' substituents was prepared and evaluated in an enzyme assay. To rationalize the structure-activity relationship (SAR) and enable the alignment of the nonsymmetric inhibitors, i.e., which of the P2/P2' substituents of the nonsymmetric inhibitors interact with which subsite, a CoMFA study was performed. The CoMFA model, constructed from the 18 inhibitors in this study along with seven inhibitors from previous work by our group, has successfully been used to rationalize the SAR of the cyclic sulfamide inhibitors. Furthermore, from the information presented herein, the SAR of the cyclic sulfamide class of inhibitors seems to differ from the SAR of the related cyclic urea inhibitors reported by DuPont and DuPont-Merck.

Crystallography, X-Ray↗
PubMed2006

Design, synthesis and structural analysis of novel bent DNAs containing cyclic uridylate dimer analogues.

We developed novel bent DNAs containing cyclic uridylate dimmer analogues (Figure 1, 1a-c), which possess an alkylene linkage with various length. These structural properties were revealed by fluorescence energy transfer (FRET) experiments, and their bending angles were found to be quite deep. This result suggests that our strategy can be applicable to highly refined studies to analyze various structure-specific DNA recognitions.

Bridged-Ring Compounds↗
PubMed1979

Long-lasting synaptic potentials and the modulation of synaptic transmission.

Long-lasting postsynaptic potentials (PSPs) generated by decreases in membrane conductance (permeability) have been reported in many types of neurons. We investigated the possible role of such long-lasting decreases in membrane conductance in the modulation of synaptic transmission in the sympathetic ganglion of the bullfrog. The molecular basis by which such conductance-decrease PSPs are generated was also investigated. Synaptic activation of muscarinic cholinergic receptors on these sympathetic neurons results in the generation of a slow EPSP (excitatory postsynaptic potential), which is accompanied by a decrease in membrane conductance. We found that the conventional "fast" EPSPs were increased in amplitude and duration during the iontophoretic application of methacholine, which activates the muscarinic postsynaptic receptors. A similar result was obtained when a noncholinergic conductance-decrease PSP--the late-slow EPSP--was elicited by stimulation of a separate synaptic pathway. The enhancement of fast EPSP amplitude increased the probability of postsynaptic action potential generation, thus increasing the efficacy of impulse transmission across the synapse. Stimulation of one synaptic pathway is therefore capable of increasing the efficacy of synaptic transmission in a second synaptic pathway by a postsynaptic mechanism. Furthermore, this enhancement of synaptic efficacy is long-lasting by virtue of the long duration of the slow PSP. Biochemical and electrophysiological techniques were used to investigate whether cyclic nucleotides are intracellular second messengers mediating the membrane permeability changes underlying slow-PSP generation. Stimulation of the synaptic inputs, which lead to the generation of the slow-PSPs, increased the ganglionic content of both cyclic AMP and cyclic GMP. However, electrophysiological analysis of the actions of these cyclic nucleotides and the actions of agents that affect their metabolism does not provide support for such a second messenger role for either cyclic nucleotide.

Acetylcholinesterase↗
PubMed1988

Prospective analysis of intraoperative and postoperative urinary cyclic adenosine 3',5'-monophosphate levels to predict outcome of patients undergoing reoperations for primary hyperparathyroidism.

Twenty-five consecutive patients with either persistent or recurrent symptomatic primary hyperparathyroidism after 36 prior operations were prospectively studied to compare the usefulness of intraoperative measurement of urinary cyclic adenosine monophosphate (UcAMP) levels with standard surgical procedures to predict outcome during tedious parathyroid reoperations. The criterion based on UcAMP to predict successful outcome was a 50% decline in intraoperative UcAMP levels from the median baseline level after removal of abnormal parathyroid tissue. Standard surgical criteria were resection of four abnormal glands for hyperplasia and resection of one abnormal gland and biopsy examination of one normal gland for adenoma. In 15 patients (60%) surgery was terminated on the basis of UcAMP criterion. In one patient elevated UcAMP levels never changed and correctly predicted unsuccessful surgery. In nine patients surgery was terminated on the basis of surgical criteria, and each of these patients had a successful outcome. Operative UcAMP levels dropped after the completion of the procedure in six of these latter nine patients. Three patients did not show a significant decrease in UcAMP levels despite successful surgery, and one patient displayed an early false-positive decrease in UcAMP level. The intraoperative UcAMP criterion accurately predicted outcome in 21 of 25 patients (84%). Sensitivity of the UcAMP criterion was 87% and specificity was 50%. The results indicate that by either method a reliable prediction of the outcome of reoperative parathyroid surgery may be made. Intraoperative determination of UcAMP levels will allow successful termination of the reoperation in some patients before operative identification of adequate parathyroid tissue necessary to confidently establish the pathologic diagnosis.

Cyclic AMP↗
PubMed1982

[Effects of prophylactic treatment of central nervous system leukemia in children. Analysis of CNS prophylactic treatment with cyclic high dose multichemotherapy, craniospinal irradiation, and high dose infusion of MTX].

Thirty-five children with previously untreated ALL or AUL who received CNS prophylactic therapy with 8 treatment regiments were analyzed. After eutering complete remission, patients received CNS-prophylaxis with one of the following regimens: Group A- cyclic high dose multichemotherapy plus intermittent intrathecal methotrexate (MTX); Group B-craniospinal irradiation plus intermittent intrathecal MTX; Group C-intermittent high dose intravenous MTX. Incidence of CNS-leukemia and bone marrow relapse was less frequent in Group B. EEG abnormalities were seen in 38.5% of Group A, 40% of Group B, and 28.6% of Group C respectively, but the abnormalities were transient. IQs of three groups were above 100, but IQs of CNS-leukemia patients, especially VIQs had a tendency to be low.

Adolescent↗
PubMed2004

Lengthening of double-looped tendon graft constructs in three regions after cyclic loading: a study using Roentgen stereophotogrammetric analysis.

Lengthening of a double-looped tendon graft construct used to reconstruct the anterior cruciate ligament (ACL) can result in an increase in anterior knee laxity and affect the stability of the reconstructed knee. Three possible regions where lengthening of the construct can occur are (1) the region of the tibial fixation, (2) the region of the femoral fixation, and (3) the region of the graft between the fixations. One objective of this study was to demonstrate the feasibility of using Roentgen stereophotogrammetric analysis (RSA) to determine the lengthening in each region of a double-looped graft construct subjected to cyclic loading. A second objective was to determine which region(s) contributes most to an increase in length of this graft construct. Radio-opaque markers were attached to ten grafts to measure the lengthening in each of the three regions. Each graft was passed through a tibial tunnel in a bovine tibia, looped around a rigid cross-pin, and fixed to the tibia with a Washerloc fixation device. The grafts were cyclically loaded for 225,000 cycles from 20 to 170 N. Prior to and at intervals during the cyclic loading, simultaneous radiographs were taken of the tibia and graft. RSA was used to determine the 3-dimensional coordinates of the markers from which the lengthening in each region was computed at each interval. The regions of the tibial and femoral fixations were the largest contributors to the increase in length of the graft, with maximum average values of 0.91 and 0.76 mm respectively after 225,000 cycles. The region between the fixations contributed least to lengthening of the graft, with a maximum average value of 0.23 mm. More than 90% of the lengthening in each region occurred before 100,000 cycles of loading. RSA proved to be a useful method for measuring lengthening in all three regions of the graft construct. Lengthening of the graft construct in both regions of fixation is sufficiently large that the combined contributions may cause a recurrence of instability in some knees.

Animals↗
PubMed1996

Unusual conformational preferences of beta-alanine containing cyclic peptides. VII.

In the present paper we describe the synthesis, purification, and single crystal x-ray analysis of the cyclic pentapeptide cyclo-(Pro-Phe-Phe-beta-Ala-beta-Ala). This compound crystallizes in the orthorhombic space group P2I2I2I from methanol and adopts in the solid state an unusual conformation characterized by a cis beta-Ala5-Pro1 peptide bond and by an intramolecular hydrogen bond stabilizing a C11-and a C12-ring structure. The C11 structure contains the Phe3 and the beta-Ala4 at the corner position of the turn; it is the first observation of a type II beta-turn enlargement due to the insertion of an extra methylene group of the beta-alanine residue. The rest of the molecule participates in a newly characterized C12-ring structure, which incorporates a beta-Ala residue at position i of the turn.

Amino Acid Sequence↗
PubMed1991

Cyclic retro-inverso dipeptides with two aromatic side chains. II. Conformational analysis.

The conformations of cis and trans cyclic retro-inverso dipeptides--2-[(4-hydroxy)benzyl]-5-benzyl-4,6(1H,2H,3H,5H)-pyrimidinedi one (c[mTyr-gPhe]), and 2-benzyl-5-amino-5-[(4-hydroxy)benzyl]-4,6(1H,2H,3H,5H)-pyrimidinedione (c[mTyr-gPhe]), and 2-benzyl-5-amino-5-[(4-hydroxy)benzyl]-4,6(1H,2H,3H,5H)-pyrimidinedione (c[(alpha-amino)mTyr-gPhe])--and the parent cyclic dipeptides--c[tyrosyl-phenylalanine] (cis-c[L-Tyr-L-Phe]) and c[tyrosyl-D-phenylalanine] (trans-c[L-Tyr-D-Phe])--were studied by using 1H-nmr spectroscopy and semiempirical energy calculations. In the cis compounds of all the cyclic retro-inverso and parent dipeptides, the most stable conformer has both aromatic side chains sharing the space over the backbone ring in a "face-to-face" fashion. All the trans compounds predominantly assume a "sandwich" conformation in which the two aromatic rings are folded back over the backbone ring on opposite sides. However, different conformational preferences were observed for the backbones between the retro-inverso and parent cyclic dipeptides. The parent cyclic dipeptide trans-c[L-Tyr-D-Phe] adopts two types of boat structures with different side-chain orientations in almost equal amounts: one with the Tyr side chain in a pseudoaxial position and the Phe side chain in a pseudoequatorial position, the other with the Tyr side chain in a pseudoequatorial position and the Phe side chain in a pseudoaxial position. On the other hand, the cyclic retro-inverso dipeptides trans-c[mPhe-gTyr] and trans c[mTyr-gPhe] assume only one type of boat structure in which the malonyl side chain is in a pseudoequatorial and the gem-diamino side chain is in a pseudoaxial position. In addition to the preferred conformations, the conformational energies of the C alpha--C beta bonds in the malonyl and gem-diamino residues were estimated from the temperature variation of vicinal 1H--1H coupling constants for the H--C alpha--C beta--H groupings observed for the trans isomers of cyclic retro-inverso dipeptides. The energies were evaluated to be 1.1 and 1.8 kcal mol-1 for the malonyl and gem-diamino residues, respectively. Applying these energies to the parent cyclic dipeptide trans-c[L-Tyr-D-Phe], the observed fractions of three side-chain conformations are reasonably reproduced. The conformational energies as well as conformational properties of the molecules estimated in this investigation may be useful to refine force constants for both parent and retro-inverso peptides with aromatic side chains.

Amino Acid Sequence↗
PubMed1990

Time-series analysis--cosinor analysis: a special case.

Cosinor analysis provides an accessible means of evaluating and estimating the parameter of a cyclic phenomenon. Cosinor analysis does not require that the data be equal intervals without missing data. Cosinor analysis does require that the data can reasonably be considered to take the form of a deterministic cycle with a known period.

Humans↗
PubMed2006

[Diagnostic value of anti-cyclic citrullinated peptide antibody for rheumatoid arthritis: a meta-analysis].

OBJECTIVE: To evaluate the diagnostic value of anti-cyclic citrullinated peptide (CCP) antibody for rheumatoid arthritis. METHODS: Data about RA from January 2000 to December 2005 were retrieved through Cochrane Library, Pubmed database, Excerpta Medica Database (EMBASE), OVID database, and China National Knowledge Infrastructure (CNKI), especially through the Annul of the Rheumatic Disease and relevant gray literatures, by entering the words "cyclic citrullinated peptides", "rheumatoid arthritis", "sensitivity", and "specificity". The inclusion of qualified literatures was based on the criteria for diagnostic research recommended by the Cochrane Methods Group on Screening and Diagnostic Test. Statistical analysis wes performed by employing the softwares of MATLAB and Review Manager 4, 2, and summary receiver operation characteristic (SROC) curve method. RESULTS: Twenty-two articles, 15 in English and 7 in Chinese, were extracted. The reported sensitivity of anti-CCP for the diagnosis of RA ranged from 39.2% to 84.6%, and the reported specificity ranged from 90% to 97.9%. The heterogeneity of the included articles was tested, a proper effect model was selected to calculate the pooled weighted sensitivity and specificity with 95% confidence interval for anti-CCP antibody as 77.3% (63.1%, 89.2%) and 93.85% (85.5%, 98.1%), and the positive and negative likelihood ratios as 12.0 and 0.24 respectively. The area under the curve of SROC was 0.8976, and the Q value was 0.87. The sensitivity of the patients with the duration of illness < 1 year was 43%, significantly lower than that of the patients with a duration of illness > 1 year (70.2%, P < 0.01); and the specificity of the patients with the duration of illness < 1 year was 94.2%, not significantly different from that of the patients with the duration of illness > 1 year (95.2%, P = 0.94). CONCLUSION: With relatively high sensitivity and specificity, anti-CCP antibody may be a useful parameter in the clinical diagnosis pf RA.

Arthritis, Rheumatoid↗
PubMed1995

A conformational model for cyclic beta-(1-->2)-linked glucans based on NMR analysis of the beta-glucans produced by Xanthomonas campestris.

A cyclic hexadecaglucoside containing 15 beta-(1-->2)-linkages and one alpha-(1-->6)-linkage (A. Amemura and J. Cabrera-Crespo, J. Gen. Microbiol. 132 (1986) 2443-2452) was purified from cultures of Xanthomonas campestris. The homogeneity of this glucan preparation facilitated the complete assignment of its 1H NMR spectrum and the assignment of all of the C-1 and C-2 resonances in its 13C NMR spectrum to specific residues within the glucan. The resonances (i.e., H-1, H-2, C-1 and C-2) that are closely associated with the beta-(1-->2) glucosidic bonds of this glucan are dispersed over a relatively broad chemical shift range. This chemical shift dispersion is attributed to the differences in the time-averaged geometry of individual beta-(1-->2)-linked glycosidic bonds in this glucan and is consistent with the hypothesis that these glycosidic bonds have less conformational freedom than do the glycosidic bonds in a linear beta-(1-->2)-linked glucan. The chemical shifts of H-1, H-2, C-1, and C-2 exhibit an alternating pattern when plotted as a function of their locations within the macrocyclic ring, suggesting that the glycosidic bond geometry also alternates in the glucan. A new conformational model for cyclic beta-(1-->2)-linked glucans was developed on the basis of these observations. This model is consistent with the observed spectroscopic features of all cyclic beta-(1-->2)-linked glucans known to be produced by Gram-negative bacteria.

Carbohydrate Conformation↗
PubMed2006

Cyclic fatigue resistance and three-dimensional analysis of instruments from two nickel-titanium rotary systems.

AIM: To determine how instrument design affects the fatigue life of two nickel-titanium (Ni-Ti) rotary systems (Mtwo and ProTaper) under cyclic fatigue stress in simulated root canals. METHODOLOGY: Cyclic fatigue testing of instruments was performed in stainless steel artificial canals with radii of curvature of 2 or 5 mm and an angle of curvature of 60 degrees . A total of 260 instruments were rotated until fracture occurred and the number of cycles to failure were recorded. The morphology of Ni-Ti rotary instruments was investigated by measuring the volume of millimetre slices of each instrument size starting from the tip to the shank by means of microCT analysis. The fracture surface of three representative samples of each size was analysed by scanning electron microscopy (SEM). Data were analysed by one-way anova, Holm t-test, paired t-test and linear regression; the significance was determined at the 95% confidence level. RESULTS: Cycles to failure significantly decreased as the instrument volume increased for both the radii of curvature tested (P < 0.01). The radius of curvature had a statistically significant influence on the fatigue life of the instruments (P < 0.05). Larger instruments underwent fracture in less time under cyclic stress than smaller ones. SEM evaluation showed typical features of fracture through fatigue failure. CONCLUSIONS: The metal volume in the point of maximum stress during a cyclic fatigue test could affect the fatigue life of Ni-Ti rotary instruments. The larger the metal volume, the lower the fatigue resistance.

Analysis of Variance↗
PubMed1990

Purification and chemical characterization of peptide G1, an invertebrate neuropeptide that stimulates cyclic GMP metabolism.

Bioassay analysis of extracts of the major neurosecretory structures of the American lobster have revealed several different agents with stimulatory effects on the cyclic GMP metabolism of various lobster tissues. The most potent of these is a peptide extracted from the sinus gland, a neurohemal organ found in the animal's eyestalk. This molecule, called peptide G1 (for its effects on cyclic GMP metabolism), can increase the cyclic GMP content of every lobster tissue tested, sometimes by as much as 200-fold. In this article, we describe the purification and some of the chemical properties of peptide G1. Purification was accomplished by sequential anion exchange and reverse-phase HPLC. The purified peptide is a large, extremely hydrophobic molecule. Its apparent molecular mass on a reducing sodium dodecyl sulfate-containing gel is 6.4 kDa, and its calculated molecular mass (based on an amino acid analysis of the purified material) is 8.2 kDa. Amino acid analysis reveals a high proportion of leucine and valine residues. The amino terminus of the molecule is not susceptible to Edman degradation, but sequencing studies were successfully carried out on tryptic fragments. Based on the estimated size of the molecule, these studies provide approximately 60% of the total sequence. No homologies with any previously sequenced peptide were observed, but biochemical similarities to as yet unsequenced peptides found in extracts of sinus glands from other crustaceans (hyperglycemic hormone and moult-inhibiting hormone) are described.

Amino Acid Sequence↗
PubMed1990

Conformation-activity relationships of cyclic dermorphin analogues.

A theoretical conformational analysis (molecular mechanics study) of nine cyclic tetrapeptides, structurally related to the highly mu-receptor-selective dermorphin analogue H-Tyr-D-Orn-Phe-Asp-NH2, was performed. These compounds display considerable diversity in their mu-receptor affinity and selectivity. A systematic search and subsequent energy minimization in absence of the exocyclic Tyr1 residue and Phe3 side chain revealed the constrained nature of the 11-13-membered ring structures contained in these analogues. No more than four low-energy conformers (within 2 kcal/mol of the lowest energy conformation) were found in each case. After attachment of the Tyr1 moiety and Phe3 side chain to the "bare" low-energy ring structures, a systematic search and energy minimization of these exocyclic moieties resulted in a limited number of low-energy conformational families for all compounds. Five analogues with high mu-receptor affinity--H-Tyr-D-Orn-Phe-Asp-NH2, H-Tyr-D-Orn-Phe-D-Asp-NH2, H-Tyr-D-Asp-Phe-Orn-NH2, H-Tyr-D-Asp-Phe-A2bu-NH2 (A2 bu: alpha, gamma-diaminobutyric acid) and H-Tyr-D-Cys-Phe-Cys-NH2--all showed a tilted stacking interaction between the Tyr1 and Phe3 aromatic rings in the lowest or second lowest energy conformation found. The same kind of stacking was not possible in low-energy conformers of the four analogues with poor affinity for the mu-receptor [H-Tyr-L-Orn-Phe-Asp-NH2, H-Tyr-D-Orn-D-Phe-Asp-NH2, H-Tyr-D-Orn-Phe(NMe)-Asp-NH2 [Phe(NMe): N alpha-methylphenylalanine], and H-Tyr-D-Orn-Phg-Asp-NH2 (Phg: phenylglycine)].(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

beta-Alanyl-beta-alanine in cyclic beta-turned peptides.

In the present paper we describe the synthesis, purification, and single crystal x-ray analysis of the cyclic pentapeptide cyclo-(L-Pro-L-Pro-L-Phe-beta-Ala-beta-Ala). The peptide was synthesized by classical solution methods and the cyclization of the free pentapeptide was accomplished in good yields in diluted methylene-chloride solution using N,N-dicyclohexylcarbodiimide. The compound crystallizes in the monoclinic space group P21 from hot water with five solvent molecules. The Pro1-Pro2 peptide bond is cis and the molecular conformation is stabilized by an intramolecular hydrogen bond between the CO group of the beta-Ala5 and the NH of the Phe3 residue. The Pro1-Pro2 segment occupies the relative positions 2 and 3 of a type VIa beta-turn, while the L-phenylalanyl-beta-alanyl-beta-alanine segment is incorporated in a C13-like ring structure. The crystal packing is characterized by a network of 11 intermolecular hydrogen bonds involving all the remaining CO, NH, and the water molecules.

Crystallography↗