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  • Review Article
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Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model

Key Points

  • In addition to the 'traditional' actions of steroid-hormone–receptor complexes — functioning in the cell nucleus as transcription factors to selectively modulate gene expression (that is, to generate genomic responses) — steroid hormones also show an essential type of action referred to as 'rapid actions' (also callled non-genomic responses).

  • The superfamily of nuclear receptors can accommodate both relatively rigid ligands as well as conformationally flexible ligands. Examples of the influence of ligand shape and flexibility on the ability to satisfy the requirements of the receptor's ligand-binding domain for genomic or rapid responses are presented.

  • Whereas the location of the ligand–receptor complex for gene transcriptional responses is in the nucleus, for most, if not all, rapid responses, the ligand–receptor complex is believed to be associated with the plasma membrane of the cell or in the very near vicinity.

  • Several possibilities for how a steroid hormone could interact with membrane receptors to generate second messengers linked to variety of signal-transduction systems are discussed. A conformational ensemble model for one possibility — that a classic steroid nuclear receptor can accommodate differently shaped ligands so as to result in the initiation of either rapid or genomic responses — is proposed.

Abstract

Steroid hormones can act as chemical messengers in a wide range of species and target tissues to produce both slow genomic responses, and rapid non-genomic responses. Although it is clear that genomic responses to steroid hormones are mediated by the formation of a complex of the hormone and its cognate steroid-hormone nuclear receptor, new evidence indicates that rapid responses are mediated by a variety of receptor types associated with the plasma membrane or its caveolae components, potentially including a membrane-associated nuclear receptor. This review summarizes our current knowledge of membrane-associated steroid receptors, as well as details of structure–function relationships between steroid hormones and the ligand-binding domains of their nuclear and membrane-associated receptors. Furthermore, a new receptor conformational ensemble model is presented that suggests how the same receptor could produce both rapid and genomic responses. It is apparent that there is a cornucopia of new drug development opportunities in these areas.

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Figure 1: Pathways for generating biological responses by steroid hormones.
Figure 2: Structures of naturally occurring hormones.
Figure 3: Structural diversity of ligand shapes accommodated by steroid-hormone receptors.
Figure 4: Schematic diagram of a steroid hormone interacting with four classes of membrane receptors to generate second messengers linking to variety of signal-transduction systems.
Figure 5: Ligand-binding domain structures.
Figure 6: Details of the ligand-binding domain in the ribbon structures of the VDR and ER-α.
Figure 7: Schematic of a receptor ensemble model to describe how a classic steroid receptor could accommodate differently shaped ligands that result in the initiation of either rapid responses or genomic responses.

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Acknowledgements

A.W.N. and M.T.M. contributed equally to the preparation of this review. Work in the laboratory of A.W.N. was supported by NIH grant DK-09012. The authors thank H. Henry for her critical review of the manuscript, and D. Keidel for his help in the initial modelling experiments and helpful conversation.

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DATABASES

LocusLink

AR

DBP

epidermal growth factor receptor

ER

MAP kinase-1

MAP kinase-3

MR

SHBG

SRC kinase

VDR

FURTHER INFORMATION

Signal Transduction Knowledge Environment website

Glossary

NATURALLY OCCURING LIGANDS

Steroid hormones are classified chemically on the basis of the traditional presence of a four-membered ring structure, A, B, C, D, which is related to cyclopentanoperhydrophenanthrene; see as an example the structure of 17β-oestradiol in figure 2b. 1α, 25(OH)2-vitamin D3 is technically a seco-steroid, which indicates that one of its rings is 'broken'; in the case of 1α, 25(OH)2-vitamin D3, the 9, 10 carbon bond is broken, which creates a conformationally flexible molecule; see figure 2a. The brassinolide steroid shown in figure 2b has an expanded seven-membered B ring.

SUPERFAMILY OF NUCLEAR HORMONE RECEPTORS

Originally, the family of steroid hormones included only oestradiol, testosterone, progesterone, cortisol, aldosterone and ecdysone. However, with the discovery of a nuclear receptor for the primary metabolite of vitamin D3, 1α, 25(OH)2-vitamin D3 in 1969, it became classified as a steroid hormone. As a consequence of cloning the protein receptors, the classes of ligands for the superfamily of nuclear receptors was further expanded beyond steroids to include thyroid hormone (3, 5, 3′-L-triodothyronine) and all trans-retinoic acid.

CONNOLLY REPRESENTATIONS

An illustration of the three-dimensional shape of the collective electron orbits of a molecule (ligand). Accordingly, a Connolly shape also defines the volume of receptor space minimally required to accommodate (or 'accept') that molecule as a bound ligand.

CAVEOLAE

Caveolae are small, flask-shaped invaginations located in the plasma membranes of many cell types; these domains have high proportions of sphingolipids and cholesterol as well as characteristic integral membrane protein, either caveolin-1, -2 or -3 (22 kDa).

ORPHAN RECEPTOR

In this case, a receptor whose structure makes it a member of the superfamily of steroid receptors, but for which no ligand has yet been identified.

CPK COLOURING

The CPK colour scheme for elements is based on the colours of the popular plastic space-filling models developed by Corey, Pauling and Kultun, and is conventionally used by chemists. In this scheme, carbon is represented in light grey, oxygen in red, nitrogen in blue and sulphur in yellow.

PLASMA TRANSPORT PROTEINS

In addition to the vitamin-D-binding protein and the sex-hormone-binding globulin, there are plasma transport proteins for the following hormones: retinoids (retinol- binding proteins), the thyroid hormones (thyroxine-binding globulin), and glucocorticoids and progesterone (corticosteroid-binding globulin). Each plasma transport protein binds its ligands with high affinity; the Kd values fall in the range 5–500 nM. In general, for any given hormone, the Kd of the hormone for its target organ receptor is 10–100 times stronger than for its plasma transport protein, for example, 0.05–50 nM.

LOCK AND KEY MODEL

In the 'lock and key' model of ligand binding, ligand-binding sites of proteins are rigid and complementary in shape to their ligand.

INDUCED FIT MODEL

Koshland's 'induced fit' hypothesis proposes that a flexible interaction between a ligand and the protein induces a conformational change in the protein, resulting in its increased ligand-binding affinity.

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Norman, A., Mizwicki, M. & Norman, D. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nat Rev Drug Discov 3, 27–41 (2004). https://doi.org/10.1038/nrd1283

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