Structural basis for inhibition of human PNP by immucillin-H

Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides. PNP is a target for inhibitor development aiming at T-cell immune response modulation. This work reports on the crystallographic study of the complex of human PNP-immucillin-H (HsPNP-ImmH) solved at 2.6 Angstrom resolution using synchrotron radiation. Immucillin-H (ImmH) inhibits the growth of malignant T-cell lines in the presence of deoxyguanosine without affecting non-T-cell tumor lines. ImmH inhibits activated normal human T cells after antigenic stimulation in vitro. These biological effects of ImmH suggest that this agent may have utility in the treatment of certain human diseases characterized by abnormal T-cell growth or activation. This is the first structural report of human PNP complexed with immucillin-H. The comparison of the complex HsPNP-ImmH with recent crystallographic structures of human PNP explains the high specificity of immucillin-H for human PNP. (C) 2003 Elsevier B.V. All rights reserved.

Structural basis for metal ion coordination and the catalytic mechanism of sphingomyelinases D

Sphingomyelinases D (SMases D) from Loxosceles spider venom are the principal toxins responsible for the manifestation of dermonecrosis, intravascular hemolysis, and acute renal failure, which can result in death. These enzymes catalyze the hydrolysis of sphingomyelin, resulting in the formation of ceramide 1-phosphate and choline or the hydrolysis of lysophosphatidyl choline, generating the lipid mediator lysophosphatidic acid. This report represents the first crystal structure of a member of the sphingomyelinase D family from Loxosceles laeta (SMase I), which has been determined at 1.75-angstrom resolution using the quick cryo-soaking technique and phases obtained from a single iodine derivative and data collected from a conventional rotating anode x-ray source. SMase I folds as an (alpha/beta)(8) barrel, the interfacial and catalytic sites encompass hydrophobic loops and a negatively charged surface. Substrate binding and/or the transition state are stabilized by a Mg2+ ion, which is coordinated by Glu(32), Asp(34), Asp(91), and solvent molecules. In the proposed acid base catalytic mechanism, His(12) and His(47) play key roles and are supported by a network of hydrogen bonds between Asp(34), Asp(52), Trp(230), Asp(233), and Asn(252).

Structural basis for branching-enzyme activity of glycoside hydrolase family 57: Structure and stability studies of a novel branching enzyme from the hyperthermophilic archaeon Thermococcus Kodakaraensis KOD1

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Crystal Structures of Xanthomonas Small Heat Shock Protein Provide a Structural Basis for an Active Molecular Chaperone Oligomer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Metabolite fingerprint of "capim dourado" (Syngonanthus nitens), a basis of Brazilian handcrafts

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Myocyte necrosis is the basis for fibrosis inrenovascular hypertensive rats

The pathogenesis of fibrosis and the functional features of pressure overload myocardial hypertrophy are still controversial. The objectives of the present study were to evaluate the function and morphology of the hypertrophied myocardium in renovascular hypertensive (RHT) rats. Male Wistar rats were sacrificed at week 4 (RHT4) and 8 (RHT8) after unilateral renal ischemia (Goldblatt II hypertension model). Normotensive rats were used as controls. Myocardial function was analyzed in isolated papillary muscle preparations, morphological features were defined by light microscopy, and myocardial hydroxyproline concentration (HOP) was determined by spectrophotometry. Renal artery clipping resulted in elevated systolic arterial pressure (RHT4: 178 ± 19 mmHg and RHT8: 194 ± 24 mmHg, P<0.05 vs control: 123 ± 7 mmHg). Myocardial hypertrophy was observed in both renovascular hypertensive groups. The myocardial HOP concentration was increased in the RHT8 group (control: 2.93 ± 0.38 µg/mg; RHT4: 3.02 ± 0.40 µg/mg; RHT8: 3.44 ± 0.45 µg/mg of dry tissue, P<0.05 vs control and RHT4 groups). The morphological study demonstrated myocyte necrosis, vascular damage and cellular inflammatory response throughout the experimental period. The increased cellularity was more intense in the adventitia of the arterioles. As a consequence of myocyte necrosis, there was an early, local, conjunctive stroma collapse with disarray and thickening of the argyrophilic interstitial fibers, followed by scarring. The functional data showed an increased passive myocardial stiffness in the RHT4 group. We conclude that renovascular hypertension induces myocyte and arteriole necrosis. Reparative fibrosis occurred as a consequence of the inflammatory response to necrosis. The mechanical behavior of the isolated papillary muscle was normal, except for an early increased myocardial passive stiffness

GCHF basis sets and their application in the electronic structure study of PrMnO3

The approach called generator coordinate Hartree-Fock (GCHF) method is used in the selection of Gaussian basis set [25s18p for O ((3)p), 31s21p14d for Mn (S-6), and 33s22p16d9f for Pr ((4)J)] for atoms. The role of the weight functions in the assessment of the numerical integration range of the GCHF equations is shown. These basis sets are contracted to (25s18p/9s5p), (31s21p14d/9s6p4d), and (33s22pl6d9f118sl2p5d3f) by segmented contraction scheme of Dunning and they are utilized in calculations of Restricted-Open-HF (ROHF) Total and Orbital energies of the (MnO+1)-Mn-3 and (PrO+1)-Pr-1 fragments, to evaluate their quality in molecular studies. The addition of one d polarization function in the contracted (9s5p) basis set for O(P-3) atom and their application with the contracted (9s6p4d), (18s21p5d3f) basis sets for Mn (S-6) and Pr-Pr ((4)j) atoms lead to the electronic structure study of PrMnO3. The dipole moment, the total energy, and total atomic charges properties were calculated and were carried out at ROHF level with the [PrMnO3](2) fragment. The calculated values show that PrMnO3 does not present piezoelectric properties. (C) 2004 Elsevier B.V. All rights reserved.

Gaussian basis sets to the theoretical study of the electronic structure of perovskite (LaMnO3)

The Generator Coordinate Hartree-Fock (GCHF) method is applied to generate extended (20s14p), (30s19p13d), and (31s23p18d) Gaussian basis sets for the 0, Mn, and La atoms, respectively. The role of the weight functions (WFs) in the assessment of the numerical integration range of the GCHF equations is shown. These basis sets are then contracted to [5s3p] and [11s6p6d] for 0 and Mn atoms, respectively, and [17s11p7d] for La atom by a standard procedure. For quality evaluation of contracted basis sets in molecular calculations, we have accomplished calculations of total and orbital energies in the Hartree-Fock-Roothaan (HFR) method for (MnO1+)-Mn-5 and (LaO1+)-La-1 fragments. The results obtained with the contracted basis sets are compared with values obtained with the extended basis sets. The addition of one d polarization function in the contracted basis set for 0 atom and its utilization with the contracted basis sets for Mn and La atoms leads to the calculations of dipole moment and total atomic charges of perovskite (LaMnO3). The calculations were performed at the HFR level with the crystal [LaMnO3](2) fragment in space group C-2v the values of dipole moment, total energy, and total atomic charges showed that it is reasonable to believe that LaMnO3 presents behaviour of piezoelectric material. (C) 2003 Elsevier B.V. All rights reserved.

The generator coordinate Hartree-Fock method as strategy for building Gaussian basis sets to ab initio study of the process of adsorption of sulfur on platinum (200) surface

The scheme named generator coordinate Hartree-Fock method (GCHF) is used to build (22s14p) and (33s22p16d9f) gaussian basis sets to S ((3)P) and Pt ((3)D) atoms, respectively. Theses basis sets are contracted to [13s10p] and [19s13p9d5f] through of Dunning's segmented contraction scheme and are enriched with d and g polarization functions, [13s10p1d] and [19s13p9d5flg]. Finally, the [19s13p9d5f1g] basis Set to Pt ((3)D) was supplemented with s and d diffuse functions, [20s13p10d5flg], and used in combination with [13s10p1d] to study the effects of adsorption of S ((3)D) atom on a pt ((3)D) atom belonged to infinite Pt (200) surface. Atom-atom overlap population, bond order, and infrared spectrum of [pt(_)S](2 -) were calculated properties and were carried out at Hartree-Fock-Roothaan level. The results indicate that the process of adsorption of S ((3)P) on pt ((3)D) in the infinite Pt (200) surface is mainly caused by a strong contribution of sigma between the 3p(z) orbital of S ((3)P) and the 6s orbital of pt ((3)D). (c) 2004 Elsevier B.V. All rights reserved.

Design of Gaussian basis sets to the theoretical interpretation of IR-spectrum of hexaaquachromium (III) ion, tetraoxochromium (IV) ion, and tetraoxochromium (VI) ion

The Generator Coordinate Hartree-Fock (GCHF) method is employed to design 16s, 16s10p, 24s17p13d, 25s17p13d, and 26s17p Gaussian basis sets for the H ((2)S), O ((3)P), O(2-) ((1)S), Cr(3+) ((4)F), Cr(4+) ((3)F), and Cr(6+) ((1)S) atomic species. These basis sets are then contracted to (4s) for H ((2)S), (6s4p) for O ((3)P), and O(2-) ((1)S), (986p3d) for Cr(3+) ((4)F), (10s8p3d) for Cr(4+) ((3)F), and (13s7p) for Cr(6+) (1S) by a standard procedure. For evaluation of the quality of those basis sets in molecular calculations, we have accomplished studies of total and orbital (HOMO and HOMO-1) energies at the HF-Roothaan level for the molecular species of our interest. The results obtained with the contracted basis sets are compared to the values obtained with our extended basis sets and to the standard 6-311G basis set from literature. Finally, the contracted basis sets are enriched with polarization function and then utilized in the theoretical interpretation of IR-spectrum of hexaaquachromium (III) ion, [Cr(H(2)O)(6)](3+), tetraoxochromium (IV) ion, [CrO(4)](4-), and tetraoxochromium (VI) ion, [CrO(4)](2-). The respective theoretical harmonic frequencies and IR-intensities were computed at the density functional theory (DFT) level. In the DFT calculations we employed the Becke's 1988 functional using the LYP correlation functional. The comparison between the results obtained and the corresponding experimental values indicates a very good description of the IR-spectra of the molecular ions studied, and that the GCHF method is still a legitimate alternative for selection of Gaussian basis sets. (C) 2003 Elsevier B.V. All rights reserved.

Structural Basis for Interaction of Inhibitors with Cyclin-Dependent Kinase 2

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Basis sets applied to the theoretical study of the vibrational structure of hexaaquaaluminum(III) ion

Gaussian basis sets were developed with the Generator Coordinate Hartree-Fock (GCHF) method for the atoms from H (14s), O (23s16p), and Al (29sl9p) in the ground state. These basis sets were then contracted to 3s (12,1,1), 5s3p (18,2,1,1,1/14,1,1), and 7s5p (20,3,2,1,1,1,1/14,2,1,1,1) for H, O and Al atoms, respectively, by a standard procedure. The quality of contracted basis sets in molecular calculations was evaluated through studies of the total and orbital (epsilon(HOMO) and epsilon(HOMO-1)) energies at the HF level for the hexaaquaaluminum(III) ion, [AI(H(2)O)(6)](3+). For the O atom, the 5s3p was supplemented with d polarization function and it was used in combination with 3s, and 7s5p for H and Al atoms was used to the theoretical interpretation of the Infrared (IR) spectrum of hexaaquaaluminum(III) ion. The calculations of the IR-spectrum were also performed at the HF level and it showed that the basis sets obtained with the aid of GCHF method lead to the selection of useful contracted Gaussian basis sets for the theoretical study of vibrational property of ionic specie of our interest. (C) 2004 Elsevier B.V. All rights reserved.

All electron fully relativistic Dirac-Fock calculation for darmstadtium carbide using prolapse free basis set

For the first time, ab inito all electron fully relativistic and correlated Dirac-Fock calculations with prolapse free basis set are reported for a Super Heavy Element. We investigated the relativistic effects on bonding and on some spectroscopic constants for the darmstadtium carbide and our results at DF/CCSD(T) with a prolapse free basis set suggest for R-e, omega(e) and D-e the values of 174 pm, 1114 cm(-1) and 7.29 eV, respectively. These values are very similar to the values for PtC found on literature. It was also found that prolapse free basis set may be important to estimate the dissociation energy using Relativistic 4-components correlated methods. (c) 2007 ELsevier B.V. All rights reserved.