Abstract
Mutations to nuclear and steroid hormone receptors (NHRs) are associated with a variety of human genetic diseases (1–3). These mutations generally result in reduced ligand binding or impaired ligand-dependent transactivation (or trans-repression) response. Individuals having mutant receptors that show reduced hormone responsiveness can often be treated with high doses of the natural hormone, however, often supraphysiological doses of hormone can create undesirable side effects that can be ascribed to inappropriate activation of other receptor subtypes and/or other samehormone responsive receptors (4, 5). In such cases hormone analogs have been empirically been used which may be able to impart greater potency activity and selectivity with mutant receptors. Thus far the use of hormone analogs for the functional rescue of impaired receptors has been largely empirical. The high-resolution structures of nuclear receptors may provide the basis to use rational molecular design strategies to efficiently create custom-designed hormone analogs, which may be able to bind to mutant receptors with greater activity, potency and selectivity than the natural hormone or existing hormone analogs. Currently relatively few examples of molecular complementation are known. This chapter will discuss examples from related nuclear receptors and other non-NHR examples to provide perspective to this exciting new area of research.
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Koh, J.T., Putnam, M.C. (2004). Towards the Rational Design of Hormone Analogs Which Complement Receptor Mutations. In: Beck-Peccoz, P. (eds) Syndromes of Hormone Resistance on the Hypothalamic-Pituitary-Thyroid Axis. Endocrine Updates, vol 22. Springer, Boston, MA. https://doi.org/10.1007/978-1-4020-7852-1_8
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DOI: https://doi.org/10.1007/978-1-4020-7852-1_8
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