5LGA

Structural analysis and biological activities of BXL0124, a Gemini analog of Vitamin D

Summary for 5LGA

• Entry DOI: 10.2210/pdb5lga/pdb
• Descriptor: Vitamin D3 receptor A, SRC-2, (1~{R},3~{S},5~{Z})-5-[2-[(1~{R},3~{a}~{S},7~{a}~{R})-7~{a}-methyl-1-[(6~{R})-1,1,1-tris(fluoranyl)-10-methyl-2,10-bis(oxidanyl)-2-(trifluoromethyl)undeca-3,8-diyn-6-yl]-2,3,3~{a},5,6,7-hexahydro-1~{H}-inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol, ... (4 entities in total)
• Functional Keywords: vitamin d nuclear receptor, agonist, gemini, transcription
• Biological source: Danio rerio (Zebrafish); More
• Cellular location: Nucleus: Q9PTN2
• Total number of polymer chains: 2
• Total formula weight: 36099.06

Authors

Belorusova, A.Y.,Rochel, N. (deposition date: 2016-07-06, release date: 2016-10-19, Last modification date: 2024-01-10)

Primary citation

Belorusova, A.Y.,Suh, N.,Lee, H.J.,So, J.Y.,Maehr, H.,Rochel, N.
Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D.
J. Steroid Biochem. Mol. Biol., 173:69-74, 2017

PubMed Abstract: Gemini analogs of calcitriol, characterized by the extension of the C21-methyl group of calcitriol with a second chain, act as agonists of the vitamin D receptor (VDR). This second side chain of gemini is accommodated in a new cavity inside the VDR created by the structural rearrangement of the protein core. The resulting conformational change preserves the active state of the receptor and bestows gemini compounds with biological activities that exceed those of calcitriol. Of particular interest are gemini's anti-cancer properties, and in this study we demonstrate anti-proliferative and tumor-reducing abilities of BXL0124 and BXL0097, differing only by the presence or absence, respectively, of the methylene group on the A ring. BXL0124 acts as a more potent VDR agonist than its 19-nor counterpart by activating VDR-mediated transcription at lower concentrations. In a similar manner, BXL0124 is more active than BXL0097 in growth inhibition of breast cancer cells and reduction of tumor volume. Structural comparisons of BXL0097 and BXL0124, as their VDR complexes, explain the elevated activity of the latter.

PubMed: 27650654
DOI: 10.1016/j.jsbmb.2016.09.015

Experimental method

X-RAY DIFFRACTION (2.5 Å)