Biomedical subjects

W L Duax

Publications and source records attributed to W L Duax.

At least 19 recordsLinked to original sources

PubMed1992

Structure of 5 beta-pregnane-3 alpha, 6 alpha, 17 alpha-triol triacetate.

C27H40O7, M(r) = 476.61, monoclinic, P2(1), a = 17.440 (5), b = 13.267 (1), c = 12.168 (2) A, beta = 110.49 (8) degrees, V = 2637.3 (9) A3, Z = 4, Dx = 1.20 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu = 7.04 cm-1, F(000) = 1032, T = 293 K, R = 0.048, wR = 0.068 for 5590 observed reflections with (Fo)2 > 2 sigma [(Fo)2]. The structure contains two crystallographically independent molecules in the asymmetric unit that have almost identical geometry. Rings A, B and C have chair conformations and the D ring assumes a half-chair conformation in both molecules. The progesterone side chain has a conformation typical for other 17 alpha-ester steroids; the C(16)--C(17)--C(20--O(20) torsion angles are -18.2 (5) and -15.0 (4) degrees for the first and the second molecule respectively.

Molecular Structure↗

PubMed1992

Structure of 6-fluoro-1 beta,2 beta-methylene-3,20-dioxo-9 beta,10 alpha-pregna-4,6-dien-17 alpha-yl acetate.

C24H29FO4, Mr = 400.5, orthorhombic, P2(1)2(1)2(1), a = 12.207 (1), b = 14.715 (1), c = 11.572 (1) A, V = 2078.7 (5) A3, Z = 4, Dx = 1.28 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu = 7.62 cm-1, F(000) = 856, T = 291 K, final R = 0.041 for 2230 observed reflections. The A and B rings assume flat boat and 9 beta,10 alpha-half-chair conformations, with asymmetry parameters delta C3s = 1.5, delta C1,2s = 11.2 and delta C6,7(2) = 3.1, delta C7s = 15.0, respectively.

Chemical Phenomena↗

PubMed1992

Molecular structure of cyclo[-(D-Val-L-Hyi-L-Val-D-Hyi)2-] revealed by x-ray analysis.

The crystal structure of a synthetic analogue of valinomycin, cyclo[-(D-Val-L-Hyi-L-Val-D-Hyi)2-] (octa-meso-valinomycin) (I) (C40H68N4O12.1.5.C4H8O2, M(r) = 937.01 + 88.10), has been determined. Crystals grown from dioxane are monoclinic, space group P2(1)/a, with cell parameters a = 21.487 (8), b = 16.836 (5), c = 16.089 (4) A, beta = 111.70 (4), and Z = 4. The atomic coordinates for nonhydrogen atoms were refined in the anisotropic thermal motion approximation. H atom positions were included in the structure factor calculations at their geometrically expected positions. Values of the standard and weighted R factors after refinement are 0.11 and 0.13, respectively. The conformation of the depsipeptide crystallized from dioxane is different from that crystallized from chloroform (II). The molecule adopts a rectangular shape with two type IV beta-turns containing a hydrogen bond and possesses pseudorotational symmetry. The side chains are located on the molecular periphery. The orientation of the carbonyl groups of the molecule is not conducive for efficient metal-ion coordination and in the observed conformation cannot behave as an ionophore. In the crystal the molecules form infinite chains parallel to the c axis, and are stabilized by two intermolecular hydrogen bonds that are shorter and have better geometry than the intramolecular hydrogen bonds. A phi/psi plot for dodecadepsipeptides with a (DLLD)3 sequence has well-defined areas for Val and Hyi residues only in cases when the crystals have been grown from nonpolar or medium-polar solvents. The phi/psi plot for octadepsipeptides crystallized from chloroform (II) shows this behavior also.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1992

Crystal and molecular structure of the depsipeptide ionophore hexadecaisoleucinomycin, cyclo-[(D-Ile-L-Lac-L-Ile-D-Hyi)4-] (C80H136N8O24).

The crystal structure of a synthetic depsipeptide ionophore hexadecaisoleucinomycin, cyclo [-(D-Ile-L-Lac-L-Ile-D-Hyi)4-] (C80H136N8O24), has been determined by single crystal x-ray diffraction techniques. The crystals are orthorhombic, space group P2(1)2(1)2(1), number of molecules per unit cell z = 4, and cell parameters a = 11,195, b = 17.853, c = 54.835 A. The values of the standard (R) and weighted (Rw) discrepancy factors after refinement are 0.122 and 0.135, respectively. The structure is characterized by an elongated bracelet form with a twofold axis of pseudosymmetry. It is stabilized by eight intramolecular 4----1 hydrogen bonds between the amide C = O and N - H groups. The ester carbonyls are directed toward the inside of the molecule, their oxygen atoms forming an ellipsoidal internal cavity. The side chains are located on the molecular periphery. The conformational states of hexadecaisoleucinomycin in solution are discussed in the light of the data obtained.

Amino Acid Sequence↗

PubMed1992

Inhibition of Streptomyces hydrogenans 3 alpha,20 beta-hydroxysteroid dehydrogenase by licorice-derived compounds and crystallization of an enzyme-cofactor-inhibitor complex.

Streptomyces hydrogenans 3 alpha,20 beta-hydroxysteroid dehydrogenase reduces the C20 ketone on glucocorticoids and progestins. We find that two licorice-derived compounds, glycyrrhizic acid and carbenoxolone, inhibit this enzyme with microM Kis. Inhibition is competitive, indicating that these compounds are binding at or close to the catalytic site. Carbenoxolone's high aqueous solubility and affinity for 3 alpha,20 beta-hydroxysteroid dehydrogenase enabled us to prepare crystals of a carbenoxolone-NADH-enzyme ternary complex, which preliminary X-ray analysis indicates has a crystal structure that is significantly different from that of the 3 alpha,20 beta-hydroxysteroid dehydrogenase-NADH complex. A comparison of the tertiary structures of these two complexes should prove useful in understanding this enzyme's catalytic mechanism, as well as those of two homologous enzymes, mammalian 11 beta-hydroxysteroid dehydrogenase and 15-hydroxyprostaglandin dehydrogenase that also are inhibited by carbenoxolone.

Binding Sites↗

PubMed1992

Crystal structure of valinomycin-monohydrate cage complexes crystallized from dioxane.

Valinomycin, cyclo-[(L-Val-D-Hyv-D-Val-L-Lac)3-], was crystallized from aqueous dioxane solvent as a monohydrate complex in which water molecules were found within the ion-binding cavity of the ionophore: monoclinic P2(1), a = 14.377 (3), b = 41.554 (14), c = 14.080 (3) A, beta = 118.27 (2) degrees, Z = 4. There are two non-equivalent valinomycin-water complexes and three dioxane molecules in the asymmetric unit. The ionophore molecules adopt two similar but non-identical, octahedral, bracelet, cage conformations that are a consequence of two distinct ways in which the complexed water molecules can deform the normal octahedral coordinate geometry of the metal binding site. In the first complex the water molecule forms hydrogen donor bonds to the carbonyl oxygens of two L-valine residues on one facial side of the cavity, while in the second complex the water molecule is trigonal-planar coordinate and binds to two L-valine residues on one entrant face of the cavity plus a third D-valine residue from the opposite side of the cavity.

Binding Sites↗

PubMed1992

Molecular conformation of estramustine and two analogues.

The crystal and molecular structures of estramustine and two of its analogues have been determined by X-ray crystallographic techniques (a total of three different compounds). The compounds studied are estramustine [1,3,5(10)-estratriene-3,17 beta-diol-3-N,N-bis(2'- chloroethyl)carbamate] and its monohydrate, estromustine [17-oxo-1,3,5(10)-estratriene-3-yl-N,N-bis(2'-chloroethyl)carbamate], and 17-oxo-5-androsten-3 beta-yl-N,N-bis(2'-chloroethyl)carbamate. Three views of estramustine were obtained from the study of its two crystal forms. The main structural features found are as follows: (a) the geometries of the steroid moieties are closely similar to those of the parent steroids, (b) the bonds around the nitrogen atom of the nitrogen mustard grouping lie approximately in a plane in each structure, (c) the plane through the carbon atoms of the steroid A-ring lies approximately perpendicular to the plane through the carbamate atoms in each structure, (d) the carbonyl C-O of the carbamate points to the alpha side of the steroid moiety in each structure, and (e) one chlorine atom of the nitrogen mustard grouping makes a close contact [3.13 A], in each structure, to the nitrogen atom. Hydrogen bonding to the carbamate appears to occur from the alpha side of the steroid; there is no hydrogen bonding to the nitrogen atom of the carbamate group. These structural data provide some steric explanations for the resistance of the carbamate to enzymatic hydrolysis. The long in vivo half-life of the intact estramustine molecule is a result of this stability. This is responsible for the absence of alkylating ability and the propensity of the drug to bind microtubule-associated proteins and express an antimitotic mechanism of action.

Estramustine↗

PubMed1991

Three-dimensional structure of holo 3 alpha,20 beta-hydroxysteroid dehydrogenase: a member of a short-chain dehydrogenase family.

The x-ray structure of a short-chain dehydrogenase, the bacterial holo 3 alpha,20 beta-hydroxysteroid dehydrogenase (EC 1.1.1.53), is described at 2.6 A resolution. This enzyme is active as a tetramer and crystallizes with four identical subunits in the asymmetric unit. It has the alpha/beta fold characteristic of the dinucleotide binding region. The fold of the rest of the subunit, the quaternary structure, and the nature of the cofactor-enzyme interactions are, however, significantly different from those observed in the long-chain dehydrogenases. The architecture of the postulated active site is consistent with the observed stereospecificity of the enzyme and the fact that the tetramer is the active form. There is only one cofactor and one substrate-binding site per subunit; the specificity for both 3 alpha- and 20 beta-ends of the steroid results from the binding of the steroid in two orientations near the same cofactor at the same catalytic site.

Amino Acid Sequence↗

PubMed1991

Structure of 9 beta-estrone.

3-Hydroxy-9 beta-estra-1,3,5(10)-trien-17-one, C18H22O2, Mr = 270.4, monoclinic, P2(1), a = 9.527 (2), b = 11.182 (3), c = 7.078 (1) A, beta = 108.45 (1) degrees, V = 715.3 (3) A3, Z = 2, Dx = 1.255 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.746 cm-1, F(000) = 292, T = 298 K, R = 0.037 for 2128 reflections with F greater than 2.0 sigma (F). The compound was one in a series of 9 beta-estrone analogues synthesized to study their estrogenic activity. The B ring conformation is a 7 beta,8 alpha-half chair, due to the configuration at C9. The O3 hydroxy forms a hydrogen bond to O17 at a distance of 2.76 A.

Estrone↗

PubMed1991

Structure of 3-hydroxy-17-oxoestra-1,3,5(10)-trien-11 beta-yl acetate.

C20H24O4, Mr = 328.41, orthorhombic, P2(1)2(1)2(1), a = 11.688 (3), b = 15.377 (5), c = 9.466 (2) A, V = 1701 (1) A3, Z = 4, Dx = 1.282 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.823 cm-1, F(000) = 704, T = 298 K, R = 0.063 for 1921 reflections with F greater than 2 sigma (F). The structure was determined to observe the effect of the 11 beta-acetate substituent on the conformation of the molecule. The 3-hydroxy is hydrogen bonded to O19 at 2.86 A. The B ring has a 7 alpha, 8 beta-half chair conformation, the most commonly observed B ring conformation in estrogen analogues.

Estrone↗

PubMed1991

Structure of 6 beta,6'beta-bi(7 alpha-allyl-3-oxo-4-estren-17 beta-yl acetate).

C46H62O6, Mr = 711.0, orthorhombic, P2(1)2(1)2(1), a = 20.187 (3), b = 22.004 (3), c = 9.180 (1) A, V = 4078 (2) A3, Z = 4, Dx = 1.16 g cm-3, lambda (Mo K alpha) = 0.71069 A, mu = 0.7 cm-1, F(000) = 1544, T = 295 K, R = 0.096 for 3894 unique observed reflections with Fo greater than 2 sigma(Fo). The title compound is a dimer connected by a single bound between C6 and C6' [bond length 1.560 (7) A]. The two steroid moieties are oriented beta-face to beta-face, head to head and lie in almost parallel planes (7.6 degrees), rotated by 45 degrees to one another. The two conformations of the identical portions of the dimer differ chiefly in the orientation of the allyl and acetate groups. C23' (acetate) and O3' form the shortest intermolecular contact less than 3.5 A; C...O = 3.35 (1) A.

Allyl Compounds↗

PubMed1991

Structure of 6 alpha-methylprogesteron-17 alpha-yl pivalate.

C27H40O4, Mr = 428.6, orthorhombic, P2(1)2(1)2(1), a = 9.821(3), b = 25.766(6), c = 9.802(3) A, V = 2480(2) A3, Z = 4, Dx = 1.15 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 0.70 cm-1, F(000) = 936, T = 295 K, final R = 0.063 for 2778 observed reflections. The A ring assumes a normal 1 alpha,2 beta-half-chair conformation. The progesterone side chain has a conformation typical of 17 alpha-ester steroids; the C(16)-C(17)-C(20)-O(20) torsion angle is -17.9(5) degrees.

Molecular Structure↗

PubMed1991

The structure of [D-Hyi2,L-Hyi4]meso-valinomycin revealed by X-ray analysis.

Direct x-ray analysis has been used to determine the crystal structure of [D-Hyi2, L-Hyi4]meso-valinomycin (cyclo[-D-Val-D-Hyi-L-Val-L-Hyi-(D-Val-L-Hyi-L-Val-D-+ ++Hyi)2-], C60H102N6O18), which crystallized from acetone with two solvent molecules. The crystals are trigonal, space group P32, number of molecules per unit cell Z = 3, cell parameters a = b = 15.2085 (8) A, c = 29.3250 (9) A, gamma = 120 degrees. The standard (R) and weighted (Rw) reliability factors after refinement of the atomic coordinates for C, N, and O atoms in the anisotropic thermal motion approximation, allowing for isotropic H atom contributions, were 0.070 and 0.082, respectively. The molecule adopts a distorted bracelet structure which is stabilized by six N-H ... O = C 4----1 type intramolecular hydrogen bonds. The side chains predominantly occupy external pseudoaxial positions relative to the cylindrical axis of the molecule. In contrast to meso-valinomycin, only four of the six Val carbonyl oxygen atoms are directed inwards to form a coordination centre for the molecule, and the carbonyl oxygen atoms of residues D-Val1 and L-Val3 are twisted outward and point away from the centre of the molecule. Although the analogue has a partially formed ion-binding center, it is inaccessible because the hydrophobic isopropyl groups of the D-Hyi2 and L-Hyi4 residues screen the molecular cavity on both sides.

Amino Acid Sequence↗

PubMed1991

Molecular conformation of a D,L stereoisomeric analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D-Hyi)-].

The crystal structure of a synthetic analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D -Hyi)-] ([L-Val1, L-Val5]meso-valinomycin), C60H102N6O18, has been determined. Crystals grown from petroleum ether are orthorhombic, space group P2(1)2(1)2(1), with cell parameters a = 16.41(1), b = 18.76(1), c = 25.86(1) A, and Z = 4. The atomic coordinates for nonhydrogen atoms, except those of terminal carbons on one side chain, were refined in the anisotropic thermal motion approximation. The coordinate parameters of the H atoms were incorporated into the structure factor calculations at geometrically expected positions. Values of the standard and weighted R factors after refinement are 0.074 and 0.083, respectively. The crystal structure of the molecule is asymmetric and adopts a conformation with four 4----1 type and one 6----1 type intramolecular hydrogen bonds between amide nitrogens and carbonyl oxygens. Valinomycin binds potassium more than 100 times strongly than the D,L stereoisomeric analogue, as a result of a different spatial orientation of potentially interacting carbonyl groups.

Amino Acid Sequence↗

PubMed1991

Chirality of isomers of aldosterone formed in dilute alkali.

In the presence of dilute alkali at room temperature aldosterone undergoes rearrangement to form 11 beta,18:18,21-diepoxy-20,21-dihydroxy-4-pregnen-3-one (V). X-Ray crystallographic analysis demonstrates that isomers of both 18R, 20S, 21S and 18R, 20S, 21R configuration are formed rather than the 18R, 20R, 21R isomer postulated on the basis of examination of 1H-NMR spectra. The spectra appears to be consistent with the major component of the mixture. The 20S configuration observed is in agreement with the chirality assigned to the degradation product obtained when the same alkaline solution of aldosterone is subjected to reflux. The crystals of (V) are monoclinic P2(1), Z = 4 with a = 20.891(2), b = 6.3848(5), c = 16.067(2)A, beta = 122.09 degrees(1) with two molecules in the asymmetric unit. Molecule A has the 20S,21S configuration and the molecules in the second site are a mixture of the 20S, 21S and 20S, 21R configuration in the ratio of 3:2.

Aldosterone↗

PubMed1991

Crystallization and preliminary diffraction analysis of cholesterol esterase from Candida cylindracea.

Cholesterol esterase (EC 3.1.1.13) from the microorganism Candida cylindracea has been crystallized in two forms. Crystals, typically 0.30 x 0.15 x 0.10 mm in size, diffract rotating anode generated x-rays to beyond 3 A are suitable for data collection for an x-ray crystallographic investigation. A monoclinic crystal form in the space group P2(1) was found to have cell dimensions of a = 122.9 A, b = 101.0 A, c = 95.2 A and beta = 108.3 degrees. The asymmetric unit of the cell contains two dimers of 129 kDa each. A second crystal form, in the triclinic space group P1, has cell dimensions of a = 58.6 A, b = 88.7 A, c = 58.6 A, alpha = 93.3 degrees, beta = 113.8 degrees and gamma = 96.0 degrees, and has one dimer per asymmetric unit.

Candida↗

PubMed1990

Structure of 6 alpha-methyl-3,20-oxo-1,4,9(11)-pregnatrien-17 alpha-yl acetate.

C24H30O4, Mr = 382.5, orthorhombic, P2(1)2(1)2(1), a = 13.091 (2), b = 19.711 (1), c = 8.242 (1) A, V = 2126.7 (5) A3, Z = 4, Dx = 1.195 Mg m-3, lambda(Cu K alpha) = 1.54184 A, mu(Cu K alpha) = 0.56 mm-1, F(000) = 824, T = 295 K. Final R = 0.045 for 2446 unique reflections. The planar A ring is bent relative to the rest of the steroid skeleton. The B ring has a typical chair conformation and the C and D rings assume 13 beta,14 alpha-half-chair and 13 beta-envelope conformations, respectively. The conformation of the progesterone side chain is similar to the conformation observed in other 17 alpha-ester pregnanes: C16-C17-C20-O20 torsion angle -27.4 (3) degrees.

Molecular Conformation↗

PubMed1990

Structure of 3-hydroxy-1-methyl-1,3,5(10)-estratriene-11,17-dione.

C19H22O3, Mr = 298.39, orthorhombic, P2(1)2(1)2(1), a = 11.332 (6), b = 14.596 (7), c = 9.567 (4) A, V = 1582.6 (5) A3, Z = 4, D chi = 1.252 Mg m-3, lambda(Mo K alpha) = 0.71073 A, mu = 0.0778 mm-1, F(000) = 640, T = 273 K, R = 0.067 for 1762 unique observed reflections where F greater than 2 sigma (F). The structure was studied to observe the effect of 1-methyl and 11-keto substitution. The 3-hydroxyl is hydrogen bonded to O11 at 2.76 A. The B ring is in a 7 alpha, 8 beta half-chair conformation. The molecule twists about the C(9)--C(10) bond to relieve the steric interaction between the 1-methyl and 11-keto groups. The C1--C10--C9--C11 torsion angle is 55 vs 33.5 degrees, the average of 38 estradiol analogue structures.

Estrone↗