Steroid Signaling

Steroids 82 (2014) 14–22 Contents lists available at ScienceDirect Steroids journal homepage: www.elsevier.com/locate/steroids Review Steroid signaling: Ligand-binding promiscuity, molecular symmetry, and the need for gating ⇑ Richard Lathe a,b,c, , Yuri Kotelevtsev a,b,d,e a State University of Pushchino, Prospekt Nauki, Pushchino 142290, Moscow Region, Russia b Pushchino Branch of the Institute of Bio-Organic Chemistry, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia c Pieta Research, PO Box 27069, Edinburgh EH10 5YW, UK d Biomedical Centre for Research Education and Innovation (CREI), Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia e Queens Medical Research Institute, University of Edinburgh, Little France, Edinburgh EH16 4TJ, UK article info abstract Article history: Steroid/sterol-binding receptors and enzymes are remarkably promiscuous in the range of ligands they Received 14 June 2013 can bind to and, in the case of enzymes, modify – raising the question of how specific receptor activa- Received in revised form 3 December 2013 tion is achieved in vivo. Estrogen receptors (ER) are modulated by 27-hydroxycholesterol and 5a- Accepted 6 January 2014 androstane-3b,17b-diol (Adiol), in addition to estradiol (E2), and respond to diverse small molecules Available online 21 January 2014 such as bisphenol A. Steroid-modifying enzymes are also highly promiscuous in ligand binding and metabolism. The specificity problem is compounded by the fact that the steroid core (hydrogenated Keywords: cyclopentophenanthrene ring system) has several planes of symmetry. Ligand binding can be in sym- Symmetry metrical East–West (rotation) and North–South (inversion) orientations. Hydroxysteroid dehydrogen- Promiscuity Ligand-binding ases (HSDs) can modify symmetrical 7 and 11, also 3 and 17/20, positions, exemplified here by yeast 3a,20b-HSD and mammalian 11b-HSD and 17b-HSD enzymes. Faced with promiscuity and symmetry, other strategies are clearly necessary to promote signaling selectivity in vivo. Gating regulates hormone access via enzymes that preferentially inactivate (or activate) a subclass of ligands, thereby governing which ligands gain receptor access – exemplified by 11b-HSD gating cortisol access to the mineralocorticoid receptor, and P450 CYP7B1 gating Adiol access to ER. Counter-intuitively, the specificity of steroid/sterol action is achieved not by intrinsic binding selectivity but by the combination of local metabolism and binding affinity. Ó 2014 Elsevier Inc. All rights reserved. Contents 1. The paradigm: specificity of steroid–protein interactions . .................................................... 15 2. What does a steroid-binding polypeptide recognize? . ....................................................................... 15 2.1. Promiscuity of receptor binding . ............................................................................. 15 2.2. What is the primary ER ligand? . ............................................................................. 16 2.3. A further problem – steroid symmetry . ............................................................................. 16 3. Promiscuity and symmetry: steroid-metabolizing enzymes . .................................................... 17 3.1. 11b-HSD (HSD11B) . ............................................................................. 17 3.2. HSD17B10 . ................................................................................................ 17 3.3. ACAT1 – one enzyme, two binding sites, multiple ligands. ............................................................. 17 3.4. Other examples . ................................................................................................ 18 4. Lack of specificity – the need for gating . ....................................................................... 18 4.1. HSD11B and the mineralocorticoid receptor (MR) . ............................................................. 18 4.2. CYP7B1 and estrogen receptors . ............................................................................. 18 4.3. Reverse (‘positive’) gating . ............................................................................. 19 4.4. Different ligands, different effects . ............................................................................. 19 4.5. Targeted transport and delivery . ............................................................................. 20 ⇑ Corresponding author at: Pieta Research, PO Box 27069, Edinburgh EH10 5YW, UK. Tel.: +44 131 478 0684. E-mail addresses: [email protected] (R. Lathe), [email protected] (Y. Kotelevtsev). 0039-128X/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.steroids.2014.01.002 R. Lathe, Y. Kotelevtsev / Steroids 82 (2014) 14–22 15 5. Concluding remarks . .................................................................................... 20 Acknowledgments . .................................................................................... 20 References . ....................................................................................................... 20 1. The paradigm: specificity of steroid–protein interactions 2. What does a steroid-binding polypeptide recognize? The current paradigm is that steroids (and related molecules The structure of the steroid nucleus does not easily lend itself to including sterols) induce their biological effects by binding selec- highly specific molecular contacts. As shown in Fig. 1, there are few tively to cognate receptor targets (the ‘lock and key’ model). How- molecular groups in a molecule such as estradiol that permit ste- ever, there is increasing realization that the stereochemistry of reospecific interactions, raising the question of what specific con- ligand binding to nuclear receptors and metabolizing enzymes is tacts steroid receptors make with the target ligand. X-ray studies far more flexible than previously thought. This conclusion is borne have shown that, following receptor binding, steroids are largely out by evolutionary and functional studies. buried within the folded polypeptide, but the assumption that Studies on an ancient metazoon, the sponge Amphimedon queen- primary interactions are spread uniformly across the molecule slandica, revealed two nuclear hormone receptors that more closely does not appear to be correct. Instead, initial binding is likely to resemble the modern retinoid-X receptor (RXR) than the group of be driven by a small number of contacts within restricted domains true steroid receptors; it was argued that the ancestral ligand, whose of the molecule, with weak stabilizing contacts across the binding arose through a process of ‘molecular tinkering’, was possi- molecular surface – that only in a second step lead to complex bly a long-chain fatty acid [1]. True steroid-type receptors arose refolding [7]. more recently. Genome sequence comparisons have revealed that This conclusion is perhaps inevitable, regarding steroid-binding the first nuclear steroid-type receptor most closely resembled the receptors and modifying enzymes, for two reasons. First, if the estrogen receptor (ER), and studies in ancient fishes argue that gen- binding polypeptide made extensive high-affinity contacts across ome duplication then subsequently led to the evolution of a second the whole ligand then the molecule would no longer dissociate receptor that most closely resembled the progesterone receptor (PR) once a local hormone surge had abated, or following reaction com- [2,3]. Reconstruction of the putative ancestral ER-like receptor at the pletion. Second, ligand-binding specificity for modern steroids is foot of the evolutionary tree allowed demonstration that this poly- often governed by a small number of molecular differences, some- peptide responded best to E2 [3], although alternative ligands (such times a single group. If the whole molecule were to be recognized as 3-hydroxysterols) were not tested. by the binding polypeptide then the impact of a single group However, there is no relationship in the position in the evolu- would be diminished, and binding specificity would be lost. tionary tree and the chemical nature of the current ligand, leading Clearly, some compromises must be made, but it appears that ste- to the speculation that ligand-binding dependency emerged sev- roid/sterol receptors make initial high-affinity contacts with only a eral times independently [4,5] and that specific ligand binding ar- fraction of the ligand, and therefore interact with a spectrum of ose relatively late. The most likely conclusion is that early related molecules. receptors responded to a range of molecules. For example, the emergence of E2 as a selective ligand for ER must have arisen late 2.1. Promiscuity of receptor binding because there is no easy synthetic route for the generation of E2 from likely precursors. In another example, the reconstructed We define here ‘promiscuity’ as the capacity of an enzyme or ancestor of the mineralocorticoid and glucocorticoid receptors receptor to bind to (and in the case of enzymes, modify) a range (MR and GR, respectively) in jawless fishes responds best to aldo- of different substrates, often in different configurations and at dif- sterone, despite evidence that the molecule was absent at this ferent positions. The term ‘promiscuity’ has been widely used in evolutionary stage, arguing that the ancestor receptor bound to this context (e.g., [8,9]) and the concept is akin to that of

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