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R Murali

Publications and source records attributed to R Murali.

At least 55 records · Page 3Linked to original sources
PubMed1996

Molecular structure, conformational analysis, and structure-activity studies of Dendrotoxin and its homologues using molecular mechanics and molecular dynamics techniques.

Three-dimensional structures of Dendrotoxin (DtX), Toxin-I (DpI), and Toxin-K (DpK) were determined using molecular mechanics and molecular dynamics techniques. The overall molecular conformation and protein folding of the three dendrotoxins are very similar to the published crystal structures of bovine pancreatic trypsin inhibitor (BPTI) and alpha-DtX. Major secondary structural regions of the dendrotoxins are stable without much fluctuation during the dynamics simulation; the regions corresponding to the turns and bends (rich in lysines and arginines) exhibit more fluctuations. The conformational angles and the C alpha...C alpha' distances of the three disulfides (in each of the dendrotoxins) are different from each other. Comparative model building studies, involving the dendrotoxins and the proteinases, reveal that the key interactions (observed in BPTI-trypsin complex) needed for anti-protease activity are absent due to structural differences between the dendrotoxins and BPTI at the anti-protease loop; this explains the inability of the dendrotoxins to inhibit proteinases. The model also suggests that the solvent-exposed beta-turn region, rich in lysines (residues 26-28), might bind directly to the extracellular anionic sites of the receptors (K+ channels) by ionic interactions. The strikingly homologous cysteine distribution (Cys-x-x-x-Cys) in DtX, DpI, and DpK, at the C-terminus, induces the occurrence of a characteristic conformational motif, consisting of an alpha-helix (in an amphiphilic environment) stabilized by two disulfides, one involving a cysteine at the beta-strand, and the other at the N-terminus. This amphiphilic secondary structural element seems to provide the rigid frame work needed for exposing the proposed active site region of the dendrotoxins to the anionic sites of the K+ channel receptors.

Amino Acid Sequence↗
PubMed1996

Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy.

Evaluation of human histocompatibility leukocyte antigen (HLA) class II genes in 54 cases of tuberculoid leprosy (TL) and 44 controls has shown a positive association with HLA-DRB1 alleles that contain Arg13 or Arg70-Arg71. Among TL patients, 87% carry specific alleles of DRB1 Arg13 or Arg70-Arg71 as compared to 43% among controls (p = 5 x 10(-6)) conferring a relative risk of 8.8. Thus, susceptibility to TL involves three critical amino acid positions of the beta chain, the side chains of which, when modeled on the DR1 crystal structure, line a pocket (pocket 4) accommodating the side chain of a bound peptide. This study suggests that disease susceptibility may be determined by the independent contribution of polymorphic residues participating in the formation of a functional arrangement (i.e., pocket) within the binding cleft of an HLA molecule.

Alleles↗
PubMed1996

Synthetic CD4 exocyclic peptides antagonize CD4 holoreceptor binding and T cell activation.

We have developed peptide analogs to analyze precise human CD4 substructures involved in MHC class II binding. Forms of the complementarity determining-like regions (CDRs) of the D1 domain of human CD4 were reproduced as synthetic aromatically modified exocyclic (AME) analogs and tested for their ability to block CD4-MHC II interactions and T cell activation. The exocyclic derived from CDR3 (residues 82-89) of human CD4, which specifically associated with CD4 on the T cell surface to create a heteromeric CD4 complex, blocked IL-2 production and antagonized the normal function of the CD4 receptor. The approach of creating novel synthetic antagonistic receptor complexes may represent a new receptor specific pharmaceutical approach to modulate biological function.

Amino Acid Sequence↗
PubMed1996

Molecular recognition of the Lewis Y antigen by monoclonal antibodies.

The murine monoclonal antibody BR55-2 is directed against the tumor-associated antigen Lewis Y oligosaccharide. The Lewis Y core antigen is a difucosylated structure consisting of four hexose units. Analysis of binding profiles of lactoseries isomeric structures by BR55-2 suggest that the binding epitope includes the OH-4 and OH-3 groups of the beta-D-galactose unit, the 6-CH3 groups of the two fucose units and the N-acetyl group of the subterminal beta-D-N-acetylglucosamine (beta DGlcNAc). To elucidate the molecular recognition properties of BR55-2 for the Y antigen, BR55-2 was cloned, sequenced and its three-dimensional structure was examined by molecular modeling. The crystal structure of BR96, another anti-Lewis Y antibody, solved in complex with a nonoate methyl ester Lewis Y tetrasaccharide, and the lectin IV protein in complex with a Lewis b tetrasaccharide core were used as a guide to probe the molecular basis for BR55-2 antigen recognition and specificity. Our modeling study shows that BR55-2 shares similar recognition features for the difucosylated type 2 lactoseries Lewis Y structure observed in the BR96-sugar complex. We observe that a major source of specificity for the Lewis Y structure by anti-Y antibodies emanates from interaction with the beta-D-N-acetylglucosamine residue and the nature of the structures extended at the reducing site of the fucosylated lactosoamine.

Amino Acid Sequence↗
PubMed1996

Are peripheral neurectomies of value in the treatment of trigeminal neuralgia? An analysis of new cases and cases involving previous radiofrequency gasserian thermocoagulation.

The indications, advantages, complications, and benefits of peripheral neurectomy in patients with trigeminal neuralgia were studied in detail in 40 patients treated between 1982 and 1991. Twenty-eight patients had previously received radiofrequency thermocoagulation: peripheral neurectomy was performed for pain recurrence. These patients had excellent or good pain relief for at least 5 years postsurgery. Of the 12 patients who had peripheral neurectomy as their only procedure, seven had an excellent result and five had a good result. Five of the patients had recurrence of pain after 2 years but responded well to a second neurectomy. Elderly patients who experienced pain in the first and second divisions of the trigeminal distributions were the best candidates. Peripheral neurectomy is an effective, safe procedure for elderly patients who suffer from trigeminal neuralgia and have a limited life span.

Adult↗
PubMed1995

Mutagenesis of the putative alpha-helical domain of the Vpr protein of human immunodeficiency virus type 1: effect on stability and virion incorporation.

vpr is one of the auxiliary genes of human immunodeficiency virus type 1 (HIV-1) and is conserved in the related HIV-2/simian immunodeficiency virus lentiviruses. The unique feature of Vpr is that it is the only nonstructural protein incorporated into the virus particle. Secondary structural analysis predicted an amphipathic alpha-helical domain in the amino terminus of Vpr (residues 17-34) which contains five acidic and four leucine residues. To evaluate the role of specific residues of the helical domain for virion incorporation, mutagenesis of this domain was carried out. Substitution of proline for any of the individual acidic residues (Asp-17 and Glu-21, -24, -25, and -29) eliminated the virion incorporation of Vpr and also altered the stability of Vpr in cells. Conservative replacement of glutamic residues of the helical domain with aspartic residues resulted in Vpr characteristic of wild type both in stability and virion incorporation, as did substitution of glutamine for the acidic residues. In contrast, replacement of leucine residues of the helical domain (residues 20, 22, 23, and 26) by alanine eliminated virion incorporation function of Vpr. These data indicate that acidic and hydrophobic residues and the helical structure in this region are critical for the stability of Vpr and its efficient incorporation into virus-like particles.

Amino Acid Sequence↗
PubMed1995

Preliminary crystallographic data for an Fab to the melanoma-associated GD2 ganglioside, and the purification of a soluble form of this antigen.

An Fab fragment from a monoclonal antibody (ME36.1) to the melanoma-associated GD2 ganglioside has been purified and crystallized in space group P2(1) with unit-cell dimensions a = 37.6, b = 94.1, c = 67.4 A, beta = 101.0 degrees. The crystals, which grow to a size of up to 0.6 x 0.5 x 0.3 mm, diffract to 2.5 A and native data have been collected to 2.8 A resolution. The crystal density is 1.22 g ml(-1) indicating one molecule of 48 kDa per asymmetric unit and a solvent content of 51%. A soluble form of the carbohydrate was obtained from the scarce GD2 glycolipid by enzymatic digestion with ceramide-glycanase. Small co-crystals of the Fab-GD2 complex have been obtained. As ME36.1 has been used in immunotherapy to treat malignant melanoma, knowledge of its interactions with the ganglioside could increase the efficacy of these treatments.

Journal Article↗
PubMed1995

Malignant teratocarcinosarcoma of the sphenoid sinus.

We have presented the first reported case of malignant teratocarcinosarcoma arising in the sphenoid sinus treated successfully with surgery and radiation therapy. The patient shows no signs of recurrence 5 years after surgery. The combined head and neck/neurosurgical approach using complete rhinotomy and medial maxillectomy with transsphenoid/transethmoid approach is advocated for sphenoid sinus tumors of this type.

Carcinosarcoma↗
PubMed1994

The refined crystal structure of hexon, the major coat protein of adenovirus type 2, at 2.9 A resolution.

The crystal structure of hexon, the major coat protein from adenovirus type 2, has been refined at 2.9 A resolution. Hexon is a homo-trimer (molecular mass 3 x 109,077 Da) and crystallizes in the cubic space group P2(1)3, with a cell edge of 150.5 A. There are four molecules in the unit cell so that the crystallographic asymmetric unit contains one subunit of the trimer. The electron density in most regions is well-defined and 880 amino acid residues, of the 967 in this unusually long polypeptide chain, have been located and fitted. The N terminus (1 to 43) and three internal stretches (192 to 203, 270 to 291 and 444 to 453) are not defined, and a stretch (168 to 207) with unclear side-chain density is modelled as poly(Ala/Gly). The current refined model, consisting of 6943 non-hydrogen protein atoms and 85 water molecules, yields an R-factor of 19.9% for 18,176 reflections in the resolution range 5.0 to 2.9 A. The model has reasonable geometry with root-mean-square deviations from ideal bond lengths of 0.022 A and angle-related 1-3 distances of 0.056 A. The overall shape of the trimeric hexon molecule is unusual and may be divided into a pseudo-hexagonal base rich in beta-structure, and a triangular top formed from three long loops containing some secondary structure. The base contains two similar pedestal domains, P1 and P2, each of which is a flattened eight-stranded beta-barrel with the "jelly-roll greek key" topology characteristic of other viral coat proteins. P1 and P2 are related by an approximate 6-fold operation about the molecular 3-fold axis so that six barrels form the walls of the tubular hexon base. The hexon bases form close-packed p3 arrays on each facet of the icosahedral adenovirus virion. Unlike other viral capsids, the barrel axes are almost perpendicular to rather than parallel with the capsid surface. The hexon top, which consists of intimately interacting loops emerging from P1 and P2 in the base, has a triangular outline and so does not exhibit the pseudo-symmetry of the base. The structure of the hexon trimer shows how economically it meets the demands of its function as a stable protective viral coat, reveals the significance of the special features in its unusual amino acid sequence, and explains its biochemical and immunological properties. The molecule is hollow, with a large central cavity, and so has a high effective volume for its mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

Crystallization and preliminary X-ray analysis of human alpha-galactosidase A complex.

Human alpha-galactosidase A (alpha-D-galactoside galactohydrolase; EC 3.2.1.22), the glycosylated lysosomal enzyme deficient in Fabry disease, has been crystallized as a complex with the inhibitor N-6-aminohexanoyl-alpha-D-galactopyranosylamine. The "hanging drop" method of vapor diffusion was used to grow crystals from solutions containing 50 mM sodium phosphate (pH 4.0 to 4.5), 120 to 170 mM ZnCl2 and 8 to 10% polyethylene glycol 3350. X-ray diffraction data collected from these crystals indicate that the crystals belong to the orthorhombic space group C222(1) with cell dimensions of a = 93.8 A, b = 141.1 A and c = 184.4 A. The crystals diffract to a resolution of 3 A and native data have been collected to 3.5 A resolution. Assuming one dimer per asymmetric unit with a total molecular mass of 110 kDa (with oligosaccharide chains), the Matthews' coefficient is Vm = 2.77 A3/dalton corresponding to a solvent content of 55% (v/v). The self-rotation function reveals that a non-crystallographic 2-fold axis relates the subunits of each dimer.

Crystallization↗
PubMed1994

Sequence and structural analysis of murine adenovirus type 1 hexon.

The genomic region encoding the major capsid protein (hexon) of murine adenovirus type 1 (MAV-1) has been isolated and sequenced. The sequence predicts a 908 residue MAV-1 hexon protein and is flanked by a portion of the upstream pVI gene and the downstream endoproteinase gene. The order of these genes and their location in the middle of the genome are the same as those found in other adenoviruses sequenced to date. Multiple sequence alignment with the other five known hexon protein sequences reveals an overall residue identity of 51% and residue conservation of 66%. In comparison with human adenovirus type 2 (Ad2), MAV-1 hexon has major deletions between residues 141 to 170, 270 to 284 and 446 to 455. Since these regions in the Ad2 hexon are partially exposed on the outer surface of the virion, they may represent type-specific antigenic determinants. The MAV-1 hexon sequence has been modelled using the known three-dimensional structure of the Ad2 hexon. The variable regions in which the mutations, deletions and insertions occur are located in the l1 and l2 loops of the molecule that form the protruding hexon towers on the external surface of the virion.

Amino Acid Sequence↗
PubMed1993

Failures of screening and management of congenital dislocation of the hip.

We report the screening of 67,093 infants for congenital dislocation of the hip from 1980 to 1989 and compare the results with those during the preceding two decades. More dislocations have been missed at neonatal examination during the last decade (0.13% of live births). Operative treatment was needed in 54 children (0.08% of live births) some of whom had been diagnosed at birth. We discuss the reasons for the failure of neonatal screening.

Female↗
PubMed1992

Spinal cord claudication from amyloid deposition.

We describe the clinical course of an 81-year-old woman who was evaluated for worsening symptomatology of spinal cord claudication. Diagnostic studies revealed mild lumbar canal stenosis at L3-4, severe stenosis at L4-5 with a myelogram-CT scan demonstrating a complete block at this level mainly a result of a hypertrophied ligamentum flavum. At surgery, the ligamentum was found to be thickened and to be causing severe compression of the dural tube. Pathologic studies of the excised ligamentum flavum revealed extensive amyloid protein deposition. The amyloid was not further classified with further medical evaluation and followup failing to identify any conditions associated with local or systemic amyloidosis.

Aged↗
PubMed1991

Effect of temperature on the myoglobin-facilitated transport of oxygen in skeletal muscle.

An analysis of thermal effects on the facilitative transport of oxygen in skeletal muscle fibers is presented. Steady-state mass and energy transport balances are written and solved analytically or numerically using a finite-difference procedure. It is shown that no significant spatial thermal gradients exist due to internal reactions or bulk conduction effects across a muscle fiber. At typical muscle conditions, it is predicted that increased global temperature reduces the fraction of oxygenated myoglobin, increases local oxygen concentrations, and increases the percentage of oxygen flux attributed to oxy-myoglobin. The maximum supportable oxygen consumption rate, mO2max, is defined as the highest consumption rate sustainable without developing anoxic regions at the center of the fiber. By considering only temperature sensitive effects within fibers, mO2max is found to increase slightly with temperature at low temperatures. This increase is due to thermal effects on the diffusion coefficients as opposed to effects associated with the kinetics of the myoglobin-oxygen reaction. If the simulations include the temperature effect associated with oxygen solubility in blood plasma, mO2max decreases with temperature. A sensitivity analysis was performed by varying the values of relevant parameters. The maximum consumption rate was least affected by parameters associated with the kinetic and equilibrium constants and most affected by the diffusion coefficients and the concentration of myoglobin.

Animals↗
PubMed1991

Cervical spine diastematomyelia in adulthood.

Adult cervical diastematomyelia is a rare malformation and is usually associated with posterior element anomalies. A case of isolated cervical diastematomyelia, which was initially thought to be a herniated cervical disc, is described. Diagnosis and surgical management are discussed.

Adult↗
PubMed1991

Neurovascular relationships of the root entry zone of lower cranial nerves: a microsurgical anatomic study in fresh cadavers.

The study describes the microsurgical neurovascular relationships of the root entry zone of lower cranial nerves in 23 cadavers. The vessel type, frequency of contact and site of contact on the root entry zone were analysed. Three types of vascular patterns (Types I-III) were found. Facial nerve: frequency of contact 31.8%; arterial contact 92.9%, Type I (lying across) 78.9%; anterior inferior cerebellar artery in 84.6%. Glossopharyngeal nerve: frequency of contact 23.9%; arteries 54.5%, veins 45.5%; posterior inferior cerebellar artery in 83.3% and Type II (loop) 50.1%. Vagus nerve: frequency of contact 26.1%, arteries 58.3%. Types II and III (passing through) formed 42.9% each. Hypoglossal nerve: frequency of contact 78.2%; vertebral artery 88.9%. No 'grooving' on any nerve was seen. Hence, 'contact' by a vessel at the root entry zone may not be significant in the etiology of lower cranial rhizopathies.

Adolescent↗