Structure of a nucleoside analog, 3'-deoxy-2'-fluorothymidine

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How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase

The structure of the Mg(2+)-dependent enzyme human phosphoserine phosphatase (HPSP) was exploited to examine the structural and functional role of the divalent cation in the active site of phosphatases. Most interesting is the biochemical observation that a Ca(2+) ion inhibits the activity of HPSP, even in the presence of added Mg(2+). The sixfold coordinated Mg(2+) ion present in the active site of HPSP under normal physiological conditions, was replaced by a Ca(2+) ion by using a crystallization condition with high concentration of CaCl(2) (0.7 m). The resulting HPSP structure now shows a sevenfold coordinated Ca(2+) ion in the active site that might explain the inhibitory effect of Ca(2+) on the enzyme. Indeed, the Ca(2+) ion in the active site captures both side-chain oxygen atoms of the catalytic Asp20 as a ligand, while a Mg(2+) ion ligates only one oxygen atom of this Asp residue. The bidentate character of Asp20 towards Ca(2+) hampers the nucleophilic attack of one of the Asp20 side chain oxygen atoms on the phosphorus atom of the substrate phosphoserine

Structure of 1-(2-deoxy-β-D-ribopyranosyl)-5-iodouracil

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Structures of the 1-(2-deoxy-2-fluoro-beta-D-arabinopyranosyl)thymine water complex and 1-(2-deoxy-2-fluoro-beta-D-arabinopyranosyl)-5-ethyluracil

(I) 1-(2-Deoxy-2-fluoro-beta-D-arabinopyranosyl)thymine-water complex, C10H13FN2O5.H2O, M(r) = 278.24, monoclinic, P2(1), a = 8.669 (4), b = 6.395 (3), c = 10.713 (7) angstrom, beta = 103.73 (5)-degrees, V = 576.9 (6) angstrom 3, Z = 2, D(m) = 1.60, D(x) = 1.602 Mg m-3, graphite-monochromated Mo K-alpha radiation, lambda = 0.71069 angstrom, mu = 0.134 mm-1, F(000) = 292, room temperature, final R = 0.030 for 1307 unique observed [F greater-than-or-equal-to 4-sigma(F)] reflections. (II) 1-(2-Deoxy-2-fluoro-beta-D-arabinopyranosyl)-5-ethyluracil, C11H15FN2O5, M(r) = 274.25, hexagonal, P6(5), a = 10.108 (7), c = 19.48 (1) angstrom, V = 1724 (2) angstrom 3, Z = 6, D(m) = 1.54, D(x) = 1.585 Mg m-3 graphite-monochromated Mo K-alpha radiation, lambda = 0.71069 angstrom, mu = 0.127 mm-1, F(000) = 864, room temperature, final R = 0.026 for 694 unique observed [F greater-than-or-equal-to 4-sigma(F)] reflections. The geometries of molecules (I) and (II) show a close similarity. In both structures the sugar ring adopts a slightly distorted chair conformation and for both molecules the fluorine and one of the hydroxyl substituents are placed in an axial position on the ring. The N-glycosidic torsion angle chi between the pyranose ring and the pyrimidine base is oriented -ac for both molecules. The terminal C of the ethyl group in (II) deviates from the base least-squares plane. The packing in both crystals is determined by intermolecular hydrogen bonds and base-stacking forces. In (I) the solvent water is kept from being disordered by a dense network of strong hydrogen bonds. In (II) the molecules are packed in such a way that a single stranded left-handed helix is formed which resembles the structure of the 61 poly(2'-O-methylcytidine) single stranded helix. No intramolecular hydrogen bonds are present. The conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature (1983) guidelines.status: publishe

Structure of nucleoside analogs 3'-fluoro-2',3'-dideoxyuridine, 3'-fluoro-2',3'-dideoxy-5-bromouridine and 3'-azido-2',3'-dideoxy-5-bromouridine

(I) 1-(3-Fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)uracil, C9H11FN2O4, M(r) = 230.20, monoclinic, P2(1), a = 9.046 (5), b = 6.994 (4), c = 15.826 (8) angstrom, beta = 101.19 (4)-degrees, V = 982.3 (9) angstrom 3, Z = 4, D(m) = 1.56, D(x) = 1.557 Mg m-3, lambda(Mo K-alpha radiation) = 0.71073 angstrom, mu = 0.127 mm-1, F(000) = 480, T = 290 K, final R = 0.029 for 1495 unique observed reflections. The asymmetric unit contains two molecules (A and B). For molecule A: the N-glycosidic torsion angle chi has a value of -121.1 (2)degrees in the anti range; the sugar pucker is 2E with P = 165 (1)degrees and psi-m = 35 (1)degrees and the C4'-C5' conformation is + sc (synclinal) with gamma = 51.3 (3)degrees. For molecule B: the N-glycosidic torsion angle chi has a value of -150.5 (2)degrees in the anti range; the sugar pucker is 2(3)T with P = 176 (1)degrees and psi-m = 26 (1)degrees and the C4'-C5' conformation is + sc with gamma = 47.4 (3)degrees. (II) 1-(3-Fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)-5-bromouracil, C9H10BrFN2O4, M(r) = 309.09, monoclinic, P2(1), a = 5.701 (4), b = 18.192 (9), c = 10.538 (5) angstrom, beta = 95.67 (5)degrees, V = 1088 (1) angstrom 3, Z = 4, D(m) = 1.89, D(x) = 1.888 Mg m-3, lambda(Mo K-alpha) = 0.71073 angstrom, mu = 3.759 mm-1, F(000) = 616, T = 290 K, final R = 0.034 for 1597 unique observed reflections. The asymmetric unit contains two molecules (A and B). For molecule A: the N-glycosidic torsion angle chi has a value of -168.8 (6)degrees in the anti range; the sugar pucker is 3(2)T with P = 179 (1)degrees and psi-m = 31 (1)degrees and the C4'-C5' conformation is + sc with gamma = 53.9 (9)degrees. For molecule B: the N-glycosidic torsion angle chi has a value of -131.8 (7)degrees in the anti range; the sugar pucker is 2E with P = 161 (1)degrees and psi-m = 35 (1)degrees and the C4'-C5' conformation is + sc with gamma = 51.2 (9)degrees. (III) 1-(3-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)-5-bromouracil, C9H10BrN5O4, M(r) = 332.11, monoclinic, P2(1), a = 5.858 (3), b = 11.813 (6), c = 17.757 (9) angstrom, beta = 92.70 (4)degrees, V = 1227 (1) angstrom 3, Z = 4, D(m) = 1.80, D(x) = 1.797 Mg m-3, lambda(Mo K-alpha) = 0.71073 angstrom, mu = 3.332 mm-1, F(000) = 664, T = 290 K, final R = 0.027 for 1713 unique observed reflections. The asymmetric unit contains two molecules (A and B). For molecule A: the N-glycosidic torsion angle chi has a value of -168.4 (4)degrees in the anti range; the sugar pucker is 3T4 with P = 203 (1)degrees and psi-m = 33 (1)degrees and the C4'-C5' conformation is ap (antiperiplanar) with gamma = 50.5 (7)degrees. All the conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Pure Appl. Chem. (1983), 55, 1273-1280] guidelines. Base-pair formation occurs in each of the three crystal structures.status: publishe

Conformational analysis of substituent effects on the sugar puckering mode and the anti-HIV activity of 2',3'-dideoxypyrimidine nucleosides

A comparison between the conformational parameters of eleven active and inactive anti-HIV 2',3'-dideoxypyrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles chi in the anti range, have pseudorotation phase angles P well distributed over both N (C3'-endo) and S (C2'-endo and C3'-exo) type sugar conformations and have both +sc and ap C4'-C5' conformations. This means that solid state conformations characterized by P, chi and gamma do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirical quantum chemical AM 1 method. Calculations of C3'-X3' bond polarities indicate that anti-HIV activity in C3'-substituted nucleoside analogues is consistent with the presence of a positive C3'-X3' bond polarity. Exploration of the conformational space of chi vs. gamma for C3'-endo, C2'-endo and C3'-exo sugar puckering modes using the same AM1 method, reveals that although the C3'-endo (P = 10') region is about 2 kcal mol-1 lower than the C2'-endo region (P = 170-degrees), the C2'-endo sugar puckering mode is the most accessible one due to the conformational flexibility about the minima. Our results also suggest that as P increases from 10-degrees, through 170-degrees, to 210-degrees, the preferred range for gamma dramatically shifts from almost exclusively around 50-degrees (+ sc) at P = 10-degrees to almost exclusively non +sc at P = 210-degrees.status: publishe

Structural studies of modified nucleosides .5. structure of a nucleoside analog - 3'-azido-5-chloro-2',3'-dideoxyuridine

1-(3-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)-5-chlorouracil, C9H10N1N5O4, M =287.66, monoclinic, P2(1), a = 5.780 (3), b = 11.730 (6), c = 17.670 (9) angstrom, beta = 93.87 (4)-degrees, V = 1195 (1) angstrom3, Z = 4, D(m) = 1.60, D(x) = 1.598 Mg m-3, graphitemonochromated Mo K-alpha radiation, lambda = 0.71073 angstrom, mu = 0.335 mm-1, F(000) = 592, T = 290 K. Final R = 0.021 for 1982 unique observed reflections. The asymmetric unit contains two molecules (A and B). For molecule A: the N-glycosidic torsion angle chi has a value of - 128.2 (2)-degrees in the anti range; the sugar pucker is 2T3 with P = 173 (1) and psi-m = 33 (1)-degrees and the C4'-C5' conformation is +sc with gamma = 50.4 (3)-degrees. For molecule B: the N-glycosidic torsion angle chi has a value of - 168.9 (2)-degrees in the anti range; the sugar pucker is 3T4 with P = 208 (1) and psi-m = 36 (1)-degrees and the C4'-C5' conformation is ap with gamma = 170.8 (2)-degrees. The conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Pure Appl. Chem. (1983), 55, 1273-1280] guidelines. Base-pair formation occurs in the crystal structure.status: publishe

Structure of a nucleoside analogue, 3'-fluoro-2',3'-dideoxy-5-fluorouridine

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