New Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Nonsteroidal Inhibitor

Bertoletti, Nicole; Braun, Florian; Lepage, Mahalia; Möller, Gabriele; Adamski, Jerzy; Heine, A.; Klebe, G.; Marchais‐Oberwinkler, Sandrine

doi:10.1021/acs.jmedchem.6b00293

Cited by 13 publications

(32 citation statements)

References 17 publications

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“…Inhibitors are useful chemical tools, which can be used not only to characterize the binding site of an enzyme but also to get insight into the physiological role of the latter upon in vivo administration. With the exception of compound 1, which we recently presented, 5 no inhibitor has been reported for this enzyme. The crystal structure of the human 17β-HSD14 has been determined recently as the holo protein (PDB 5JS6 and 5JSF) and as the ternary complex with the nonsteroidal inhibitor 1 (PDB 5ICM).…”

Section: ■ Introductionmentioning

confidence: 76%

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First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

et al. 2016

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17β-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD as cofactor. The goal of this study was to identify and optimize 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17β-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a K equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17β-HSD1 and 17β-HSD2 is also addressed.

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Section: ■ Introductionmentioning

confidence: 76%

“…17β-HSD14 is a tetramer. 5 The binding cavity was shown to be rather lipophilic with a conical shape. The substrate active site is narrow in the vicinity of the catalytic triad and is solvent exposed at the other end.…”

Section: ■ Introductionmentioning

confidence: 99%

First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

et al. 2016

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“…Therefore, it is still unclear whether this enzyme may serve as a drug target in the future. Recently, the 3D-structures of the cytosolic protein as holo form and as ternary complexes with E1 and with a nonsteroidal inhibitor have been described (Bertoletti et al 2016;Braun et al 2016).…”

Section: Methodsmentioning

confidence: 99%

“…The crystal structure of 17β-HSD14 in complex with NAD + and 96 is the first to be obtained from a human SDR 17β-HSD enzyme with a nonsteroidal compound. The inhibitor is embedded in an extended H-bonding network and adopts a V-shaped conformation which corresponds to the active site geometry (Bertoletti et al 2016).…”

Section: Inhibitors Of 17β-hsd14mentioning

confidence: 99%

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Salah

Abdelsamie²,

Frotscher

2019

Molecular and Cellular Endocrinology

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During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.

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“…However, this extensive and open active cleft may also be due to lack of a co-crystallized substrate in the X-ray structure, and substrate binding might result in an induced fit. Evidence for an induced fit upon cofactor binding was recently provided by Bertoletti and Braun et al, who resolved the crystal structure of 17β-HSD14 as the holo form with NAD + and as ternary complexes with estrone and the first nonsteroidal inhibitor of 17β-HSD14 [181]. The residues 189-212 were found to form a flexible loop adopting a closed conformation in the presence of cofactor and reducing the size of the active site.…”

Section: Examples From the Sdr Familymentioning

confidence: 99%

Virtual screening applications in short-chain dehydrogenase/reductase research

Beck

Kaserer

Schuster

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Several members of the short-chain dehydrogenase/reductase (SDR) enzyme family play fundamental roles in adrenal and gonadal steroidogenesis as well as in the metabolism of steroids, oxysterols, bile acids, and retinoids in peripheral tissues, thereby controlling the local activation of their cognate receptors. Some of these SDRs are considered as promising therapeutic targets, for example to treat estrogen-/androgen-dependent and corticosteroid-related diseases, whereas others are considered as anti-targets as their inhibition may lead to disturbances of endocrine functions, thereby contributing to the development and progression of diseases. Nevertheless, the physiological functions of about half of all SDR members are still unknown. In this respect, in silico tools are highly valuable in drug discovery for lead molecule identification, in toxicology screenings to facilitate the identification of hazardous chemicals, and in fundamental research for substrate identification and enzyme characterization. Regarding SDRs, computational methods have been employed for a variety of applications including drug discovery, enzyme characterization and substrate identification, as well as identification of potential endocrine disrupting chemicals (EDC). This review provides an overview of the efforts undertaken in the field of virtual screening supported identification of bioactive molecules in SDR research. In addition, it presents an outlook and addresses the opportunities and limitations of computational modeling and in vitro validation methods.

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New Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Nonsteroidal Inhibitor

Cited by 13 publications

References 17 publications

First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

Virtual screening applications in short-chain dehydrogenase/reductase research

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