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      Relationship between Structure and Conformational Change of the Vitamin D Receptor Ligand Binding Domain in 1α,25-Dihydroxyvitamin D3 Signaling

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          Abstract

          Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily. Whereas the structure of the ligand binding domain (LBD) of VDR has been determined in great detail, the role of its amino acid residues in stabilizing the structure and ligand triggering conformational change is still under debate. There are 13 α-helices and one β-sheet in the VDR LBD and they form a three-layer sandwich structure stabilized by 10 residues. Thirty-six amino acid residues line the ligand binding pocket (LBP) and six of these residues have hydrogen-bonds linking with the ligand. In 1α,25-dihydroxyvitamin D 3 signaling, H3 and H12 play an important role in the course of conformational change resulting in the provision of interfaces for dimerization, coactivator (CoA), corepressor (CoR), and hTAF II 28. In this paper we provide a detailed description of the amino acid residues stabilizing the structure and taking part in conformational change of VDR LBD according to functional domains.

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          Structural determinants of allosteric ligand activation in RXR heterodimers.

          David J. Mangelsdorf, Gerald I. Shulman, Rama Ranganathan … (2004)
          Allosteric communication underlies ligand-dependent transcriptional responses mediated by nuclear receptors. While studies have elucidated many of the components involved in this process, the energetic architecture within the receptor protein that mediates allostery remains unknown. Using a sequence-based method designed to detect coevolution of amino acids in a protein, termed the statistical coupling analysis (SCA), we identify a network of energetically coupled residues that link the functional surfaces of nuclear receptor ligand binding domains. Functional analysis of these predicted residues demonstrates their participation in an allosteric network that governs the ability of heterodimeric receptors to activate transcription in response to ligand binding by either partner. Interestingly, mutation of a single network residue can discriminate between receptor activation by endocrine, dietary, and synthetic agonists. These results reveal a structural network required for RXR heterodimer allosteric communication and suggest that the specificity of ligand response and permissivity coevolved to enable signal discrimination.
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            The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand.

            B Klaholz, N Rochel, A Mitschler … (1999)
            The action of 1 alpha, 25-dihydroxyvitamin D3 is mediated by its nuclear receptor (VDR), a ligand-dependent transcription regulator. We report the 1.8 A resolution crystal structure of the complex between a VDR ligand-binding domain (LBD) construct lacking the highly variable VDR-specific insertion domain and vitamin D. The construct exhibits the same binding affinity for vitamin D and transactivation ability as the wild-type protein, showing that the N-terminal part of the LBD is essential for its structural and functional integrity while the large insertion peptide is dispensable. The structure reveals the active conformation of the bound ligand and allows understanding of the different binding properties of some synthetic analogs.
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              Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA.

              Bruno Klaholz, Dino Moras, Natacha Rochel … (2012)
              Transcription regulation by steroid hormones and other metabolites is mediated by nuclear receptors (NRs) such as the vitamin D and retinoid X receptors (VDR and RXR). Here, we present the cryo electron microscopy (cryo-EM) structure of the heterodimeric complex of the liganded human RXR and VDR bound to a consensus DNA response element forming a direct repeat (DR3). The cryo-EM map of the 100-kDa complex allows positioning the individual crystal structures of ligand- and DNA-binding domains (LBDs and DBDs). The LBDs are arranged perpendicular to the DNA and are located asymmetrically at the DNA 5'-end of the response element. The structure reveals that the VDR N-terminal A/B domain is located close to the DNA. The hinges of both VDR and RXR are fully visible and hold the complex in an open conformation in which co-regulators can bind. The asymmetric topology of the complex provides the structural basis for RXR being an adaptive partner within NR heterodimers, while the specific helical structure of VDR's hinge connects the 3'-bound DBD with the 5'-bound LBD and thereby serves as a conserved linker of defined length sensitive to mutational deletion.
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                Author and article information

                Contributors
                Derek J. McPhee: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 18 November 2015
                Publication date Collection: November 2015
                Volume: 20
                Issue: 11
                Pages: 20473-20486
                Affiliations
                [1 ]Medical College, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang 443002, China; wanlinyan0224@ 123456163.com (L.-Y.W.); zhangyanqiong@ 123456ctgu.edu.cn (Y.-Q.Z.); 15572753727@ 123456163.com (M.-D.C.); youqindu@ 123456126.com (Y.-Q.D.)
                [2 ]Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang 443002, China
                Author notes
                [* ]Correspondence: cbliu@ 123456ctgu.edu.cn (C.-B.L.); wujiangfeng@ 123456ctgu.edu.cn (J.-F.W.); Tel./Fax: +86-717-639-7179 (C.-B.L.); +86-717-639-7328 (J.-F.W.)
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: molecules-20-19713
                DOI: 10.3390/molecules201119713
                PMC ID: 6332228
                PubMed ID: 26593892
                SO-VID: 8501f2d5-8161-4bea-8a97-57e9d5756db3
                Copyright © © 2015 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 08 October 2015
                Date accepted : 11 November 2015
                Categories
                Subject: Review

                Keywords: ligand binding domain,vitamin d receptor,structure basis,functional domains,conformational change
                Data availability:
                Keywords: ligand binding domain, vitamin d receptor, structure basis, functional domains, conformational change

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