title: Molecular mechanism of activation and nuclear translocation of the mineralocorticoid receptor upon binding of pregnanesteroids.
abstract: The mineralocorticoid receptor (MR) is primarily localized in the cytoplasm of the cell in the absence of ligand. The first step in the genomic-dependent mechanism of action of mineralocorticoids is the binding of steroid to the MR, which in turn triggers MR nuclear translocation. The regulation of hormone-binding to MR is complex and involves a multifactorial mechanism, making it difficult to determine the optimal structure of a steroid for activating the MR and promoting its nuclear translocation. Here we review the structure-activity relationship for several pregnanesteroids that possess various functional groups, and suggest that a flat conformation of the ligand rather than the presence of particular chemical groups is a critical parameter for the final biological effect in vivo. We also discuss how the MR undergoes differential conformational changes according to the nature of the bound ligand, which in turn affects the dynein-dependent retrograde rate of movement for the steroid/receptor complex.
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Consejo Nacional de Investigaciones, Científicas y Técnicas, Buenos Aires, Argentina. mgali@umich.edu
authors.forename: M D
authors.initials: MD
authors.lastname: Galigniana
authors.forename: G
authors.initials: G
authors.lastname: Piwien Pilipuk
authors.forename: K C
authors.initials: KC
authors.lastname: Kanelakis
authors.forename: G
authors.initials: G
authors.lastname: Burton
authors.forename: C P
authors.initials: CP
authors.lastname: Lantos
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D011282:Pregnenediones / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D011282:Pregnenediones; D018161:Receptors, Mineralocorticoid; D014157:Transcription Factors