scholarly journals Structure of 3(17)α-hydroxysteroid dehydrogenase (AKR1C21) holoenzyme from an orthorhombic crystal form: an insight into the bifunctionality of the enzyme

2007 ◽  
Vol 63 (10) ◽  
pp. 825-830 ◽  
Author(s):  
Urmi Dhagat ◽  
Vincenzo Carbone ◽  
Roland P.-T. Chung ◽  
Clemens Schulze-Briese ◽  
Satoshi Endo ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Crystal Form ◽  
Orthorhombic Crystal ◽  
Insight Into

scholarly journals 17β-Estradiol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes

2009 ◽  
Vol 202 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Noriko Tagawa ◽  
Ryosuke Yuda ◽  
Sayaka Kubota ◽  
Midori Wakabayashi ◽  
Yuko Yamaguchi ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Fat Depots ◽  
Mesenteric Fat ◽  
17Β Estradiol ◽  
Transcriptional Pathway ◽  
Insight Into ◽  
Full Activation

17β-Estradiol (E2) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E2 on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E2 inhibited 11β-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E2 on 11β-HSD1 activity was observed within 5–10 min. Furthermore, acetylation or α-epimerization of 17-hydroxy group of E2 attenuated the inhibitory effect on 11β-HSD1. These results indicate that the inhibition of 11β-HSD1 by E2 depends on neither an ER-dependent route, transcriptional pathway nor non-specific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11β-HSD1, was unaffected by E2. A kinetic study revealed that E2 acted as a non-competitive inhibitor of 11β-HSD1. The inhibitory effect of E2 on 11β-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E2 inhibits 11β-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.

scholarly journals Two polymorphs of 1,8-dichloroanthracene

2013 ◽  
Vol 69 (2) ◽  
pp. 199-203 ◽  
Author(s):  
Peter Müller ◽  
Frank R. Fronczek ◽  
Stacey J. Smith ◽  
Teresa Mako ◽  
Mindy Levine
Keyword(s):  
Low Temperature ◽  
Crystal Packing ◽  
Three Dimensional ◽  
Crystal Form ◽  
Temperature Structure ◽  
Orthorhombic Crystal ◽  
Acta Cryst ◽  
Monoclinic Form ◽  
Compound C ◽  
Dimensional Network

A second, monoclinic, polymorph of the title compound, C14H8Cl2, has been found. In addition to the structure of this monoclinic form, the structure of the previously described orthorhombic form [Desvergne, Chekpo & Bouas-Laurent (1978).J. Chem. Soc. Perkin Trans. 2, pp. 84–87; Benites, Maverick & Fronczek (1996).Acta Cryst.C52, 647–648] has been redetermined at low temperature and using modern methods. The low-temperature structure of the orthorhombic form is of significantly higher quality than the previously published structure and additional details can be derived. A comparison of the crystal packing of the two forms with a focus on weak intermolecular C—H...Cl interactions shows the monoclinic structure to have one such interaction linking the molecules into infinite ribbons, while two crystallographically independent C—H...Cl interactions give rise to an interesting infinite three-dimensional network in the orthorhombic crystal form.

Structure of Monellin Refined to 2.3 Å Resolution in the Orthorhombic Crystal Form

1997 ◽  
Vol 53 (6) ◽  
pp. 713-719 ◽  
Author(s):  
G. Bujacz ◽  
M. Miller ◽  
R. Harrison ◽  
N. Thanki ◽  
G. L. Gilliland ◽  
...  
Keyword(s):  
Crystal Form ◽  
Orthorhombic Crystal

A New Insight Into the Molecular Basis of 3β-Hydroxysteroid Dehydrogenase Deficiency

2000 ◽  
Vol 26 (4) ◽  
pp. 761-770 ◽  
Author(s):  
Jacques Simard ◽  
Marie Louise Ricketts ◽  
Anne Marie Moisan ◽  
Veronique Tardy ◽  
Michael Peter ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Dehydrogenase Deficiency ◽  
Hydroxysteroid Dehydrogenase ◽  
Insight Into

ENDOGENOUS NEUTRAL STEROIDS IN THE LUNG TISSUE OF EARLY AND MID-TERM HUMAN FOETUSES AND IN VITRO STUDIES ON THEIR FORMATION

1974 ◽  
Vol 75 (1) ◽  
pp. 148-158 ◽  
Author(s):  
I. Huhtaniemi
Keyword(s):  
Mass Spectrometry ◽  
Lung Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Gas Liquid Chromatography ◽  
Wet Weight ◽  
Total Concentrations ◽  
Insight Into ◽  
Human Foetuses ◽  
Endogenous Steroids

ABSTRACT Four pools of lung tissue from 2 or 3 foetuses of 11–17 weeks' gestational age were analyzed by gas-liquid chromatography and gaschromatography-mass spectrometry for endogenous neutral steroids. All of the steroids detected were present as their mono- or disulphate conjugates. No free compounds were found. Dehydroepiandrosterone, pregnenolone and their 16α-hydroxylated derivatives were the compounds present in highest concentrations in the monosulphate fraction. The most prominent steroid in the disulphate fraction was 5-androstene-3β,17α-diol. Other compounds detected were the monosulphates of 3β,7α-dihydroxy-5-androsten-17-one, 3β,16β- dihydroxy -5- androsten-17-one, 3β,17β- dihydroxy-5-androsten-16-one, 5-androstene-3β,16β,1 7α-triol, 5-pregnene-3β,17α-diol, and 3β,17α-dihydroxy-5-pregnen-20-one and the disulphates of 5-androstene-3β,17β-diol, 3β,16α-dihydroxy-5-androsten-17-one and 5-pregnene-3β,20α-diol. The total concentrations of steroids in the lung tissue varied from 300 to 600 μg/100 g tissue wet weight. In order to gain some insight into the origin of the endogenous steroids detected, i. e. whether they were synthesized by the lung tissue or only filtered by it from the perfusing blood, minced lung tissue was incubated with dehydroepiandrosterone, pregnenolone, 3β,17α-dihydroxy-5-pregnen-20-one and with their sulphate conjugates. Evidence for the presence of the following enzymes was found: sulphokinase, 7α-hydroxylase, 16αhydroxylase, 17α-hydroxylase, 17β-hydroxysteroid dehydrogenase, 20α-hydroxysteroid dehydrogenase and C17–20 desmolase.

Structure of a backtracked state reveals conformational changes similar to the state following nucleotide incorporation in human norovirus polymerase

2014 ◽  
Vol 70 (12) ◽  
pp. 3099-3109 ◽  
Author(s):  
Dmitry Zamyatkin ◽  
Chandni Rao ◽  
Elesha Hoffarth ◽  
Gabriela Jurca ◽  
Hayeong Rho ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Active Site ◽  
Covalent Bond ◽  
Crystal Form ◽  
Phosphoryl Group ◽  
Nucleoside Triphosphate ◽  
Orthorhombic Crystal ◽  
Crystal Forms ◽  
Terminal Nucleotide ◽  
Thumb Domain

The RNA-dependent RNA polymerase (RdRP) from norovirus (NV) genogroup II has previously been crystallized as an apoenzyme (APO1) in multiple crystal forms, as well as as a pre-incorporation ternary complex (PRE1) bound to Mn2+, various nucleoside triphosphates and an RNA primer-template duplex in an orthorhombic crystal form. When crystallized under near-identical conditions with a slightly different RNA primer/template duplex, however, the enzyme–RNA complex forms tetragonal crystals (anisotropic data,dmin≃ 1.9 Å) containing a complex with the primer/template bound in a backtracked state (BACK1) similar to a post-incorporation complex (POST1) in a step of the enzymatic cycle immediately following nucleotidyl transfer. The BACK1 conformation shows that the terminal nucleotide of the primer binds in a manner similar to the nucleoside triphosphate seen in the PRE1 complex, even though the terminal two phosphoryl groups in the triphosphate moiety are absent and a covalent bond is present between the α-phosphoryl group of the terminal nucleotide and the 3′-oxygen of the penultimate nucleotide residue. The two manganese ions bound at the active site coordinate to conserved Asp residues and the bridging phosphoryl group of the terminal nucleotide. Surprisingly, the conformation of the thumb domain in BACK1 resembles the open APO1 state more than the closed conformation seen in PRE1. The BACK1 complex thus reveals a hybrid state in which the active site is closed while the thumb domain is open. Comparison of the APO1, PRE1 and BACK1 structures of NV polymerase helps to reveal a more complete and complex pathway of conformational changes within a single RdRP enzyme system. These conformational changes lend insight into the mechanism of RNA translocation following nucleotidyl transfer and suggest novel approaches for the development of antiviral inhibitors.

An orthorhombic crystal form of cyclohexaicosaose, CA26·32.59 H2O: comparison with the triclinic form

2001 ◽  
Vol 336 (2) ◽  
pp. 141-153 ◽  
Author(s):  
Olaf Nimz ◽  
Katrin Geßler ◽  
Isabel Usón ◽  
Wolfram Saenger
Keyword(s):  
Crystal Form ◽  
Orthorhombic Crystal ◽  
Triclinic Form

Structure of an insulin dimer in an orthorhombic crystal: the structure analysis of a human insulin mutant (B9 Ser→Glu)

1999 ◽  
Vol 55 (9) ◽  
pp. 1524-1532 ◽  
Author(s):  
Zhi-Ping Yao ◽  
Zong-Hao Zeng ◽  
Hong-Min Li ◽  
Ying Zhang ◽  
You-Min Feng ◽  
...  
Keyword(s):  
Human Insulin ◽  
Solution Structure ◽  
Building Blocks ◽  
Structural Rearrangement ◽  
Crystal Form ◽  
Terminal Segment ◽  
Orthorhombic Crystal ◽  
Amino Terminal ◽  
Cell Dimensions ◽  
Unit Cell Dimensions

The structure of human insulin mutant B9 (Ser→Glu) was determined by an X-ray crystallographic method at 2.5 Å resolution with an R factor of 0.165 under non-crystallographic restraints. The crystals were grown at low pH (<3.8) and belong to the orthorhombic P212121 space group with unit-cell dimensions a = 44.54, b = 46.40, c = 51.85 Å and one dimer per asymmetric unit without further aggregation. The structure in this crystal form can be regarded as a model for a discrete insulin dimer and displays the following features compared with the structure of 2Zn insulin. (i) The overall dimer is expanded and more symmetric. The two A chains are about 2 Å more distant from each other, while the two B chains are about 0.8 Å further apart. Both monomers are more similar to molecule 1 than molecule 2 of the 2Zn insulin dimer. (ii) The dimer structure is stabilized by protonation and neutralization of the carboxyl groups at lower pH and, in addition, by formation of a hydrogen-bond network among the side chains of residues GluB9, HisB13 and HisB10 on the dimer-forming surface of both monomers, resulting from a structural rearrangement. (iii) The B-chain amino-terminal segment is in an open state (O state), i.e. a state different from the well known R and T states found in the insulin hexamer. In the O state, the B-chain N-terminal segment is in an extended conformation and is detached from the rest of the molecule. This conformational state has also been observed in the monomeric crystal structure of despentapeptide (B26–B30) and desheptapeptide (B24–B30) insulin, as well as in the solution structure of an engineered insulin monomer. It suggests that the O state may be the characteristic conformation of insulin in lower aggregation forms and may be relevant to the formation of insulin fibrils. In addition, based on the crystallization process, the smallest possible building blocks of insulin crystal are also discussed.

Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105

2020 ◽  
Vol 16 (3) ◽  
pp. 243-250
Author(s):  
Preyesh Stephen ◽  
Jenny Roy ◽  
René Maltais ◽  
Donald Poirier
Keyword(s):  
Homology Model ◽  
Hydroxysteroid Dehydrogenase ◽  
Enzymatic Assays ◽  
Enzyme Binding ◽  
Structure Activity ◽  
Potential Binding ◽  
Competitive Action ◽  
Type 3 ◽  
Insight Into ◽  
Selection Of

Background: The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.

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