In:
Nature Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2017-10-13)
Abstract:
The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization via transcriptional control of osteocalcin ( BGLAP ) gene and is the receptor for 1α,25-dihydroxyvitamin D 3 (1,25D3). However, supra-physiological levels of 1,25D3 activates the calcium-regulating gene TRPV6 leading to hypercalcemia. An approach to attenuate this adverse effect is to develop selective VDR modulators (VDRMs) that differentially activate BGLAP but not TRPV6 . Here we present structural insight for the action of a VDRM compared with agonists by employing hydrogen/deuterium exchange. Agonist binding directs crosstalk between co-receptors upon DNA binding, stabilizing the activation function 2 (AF2) surfaces of both receptors driving steroid receptor co-activator-1 (SRC1) interaction. In contrast, AF2 of VDR within VDRM: BGLAP bound heterodimer is more vulnerable for large stabilization upon SRC1 interaction compared with VDRM: TRPV6 bound heterodimer. These results reveal that the combination of ligand structure and DNA sequence tailor the transcriptional activity of VDR toward specific target genes.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-017-00978-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2017
detail.hit.zdb_id:
2553671-0
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