Corepressor excess shifts the two-side chain vitamin D analog Gemini from an agonist to an inverse agonist of the vitamin D receptor.
نویسندگان
چکیده
The vitamin D receptor (VDR) is an endocrine nuclear receptor that binds with high affinity its natural ligand 1alpha,25-dihydroxyvitamin D3. Gemini is a 1alpha,25-dihydroxyvitamin D3 analog with two identical side chains that, despite its significantly increased volume, binds to the VDR and can function as a potent agonist. This study demonstrates that, at excess corepressor (CoR) levels, Gemini shifts from an agonist to an inverse agonist that actively recruits CoR proteins to the VDR and mediates superrepression. Under these conditions Gemini stabilizes the VDR into a silent conformation, in which helix 12 of the ligand-binding domain is repositioned and thus unable to contribute to coactivator interaction. Amino acid F422 has been described as the lock of helix 12 and seems to be the most critical VDR residue in the inverse agonistic action of Gemini. Molecular dynamics simulations of the Gemini-VDR complex support these observation by indicating that the second side chain of Gemini induces tension to the receptor structure that can be released by a shift of helix 12. Taken together, Gemini is the first described (conditional) inverse agonist to an endocrine nuclear receptor and may function as a sensor for the cell-specific coactivator/CoR ratio.
منابع مشابه
I-19: The Selective Vitamin D Receptor Agonist Elocalcitol Reduces Development of Endometriosis and Formation of Peritoneal Adhesion in A Mouse Model
Background: Endometriosis is a chronic disorder characterized by the presence of endometrial tissue outside the uterus. Endometrial cells from retrograde menstruation implant on peritoneal surfaces and elicit an inflammatory response, associated with angiogenesis, fibrosis, neuronal infiltration, and anatomical distortion. Affecting an estimated 176 million women worldwide, the condition is sti...
متن کاملAntagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein.
Ligand-dependent signal transduction by nuclear receptors (NRs) includes dynamic exchanges of coactivator (CoA) and corepressor (CoR) proteins. Here we focused on the structural determinants of the antagonist- and inverse agonist-enhanced interaction of the endocrine NR vitamin D receptor (VDR) and the adopted orphan NR constitutive androstane receptor (CAR) from two species with the CoR NR cor...
متن کاملStructural evaluation of the agonistic action of a vitamin D analog with two side chains binding to the nuclear vitamin D receptor.
The vitamin D receptor (VDR) is one of the endocrine members of the nuclear receptor superfamily and has a characteristic high affinity for its natural ligand 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. From a mechanistic point of view, the most interesting analog of 1alpha,25(OH)2D3 is the one that carries two side chains, referred to as Gemini. In this study, molecular dynamics (MD) sim...
متن کاملCombination Therapy with A1 Receptor Agonist and Vitamin C Improved Working Memory in a Mouse Model of Global Ischemia-Reperfusion
Introduction: Stroke is one of the most important reasons of death. Hence, trials to prevent or lessen the complications originated by stroke are a goal of public health worldwide. The ischemia-reperfusion causes hypoxia, hypoglycemia and incomplete repel of metabolic waste products and leads to accumulation of free radicals triggering neuronal death. The A1 adenosine receptoras an endogenous l...
متن کاملCarborane-based design of a potent vitamin D receptor agonist.
The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D3 (1,25D) and an o-carborane (dicarba-o-closo-1,2...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Molecular endocrinology
دوره 17 10 شماره
صفحات -
تاریخ انتشار 2003