3DR1

Side-chain fluorine atoms of non-steroidal vitamin D3 analogs stabilize helix 12 of vitamin D receptor

Summary for 3DR1

• Entry DOI: 10.2210/pdb3dr1/pdb
• Descriptor: Vitamin D3 receptor A, SRC-1 (LXXLL motif) from Nuclear receptor coactivator 1, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: gene regulation, dna-binding, metal-binding, nucleus, receptor, transcription, transcription regulation, zinc, zinc-finger, activator, acyltransferase, alternative splicing, chromosomal rearrangement, phosphoprotein, polymorphism, proto-oncogene, transferase, ubl conjugation, gene regulation-transferase complex, gene regulation/transferase
• Biological source: Danio rerio (zebra fish); More
• Cellular location: Nucleus: Q9PTN2; Nucleus (By similarity): Q15788
• Total number of polymer chains: 2
• Total formula weight: 36343.55

Authors

Sato, Y.,Rochel, N.,Moras, D. (deposition date: 2008-07-10, release date: 2009-06-16, Last modification date: 2023-11-01)

Primary citation

Eelen, G.,Valle, N.,Sato, Y.,Rochel, N.,Verlinden, L.,De Clercq, P.,Moras, D.,Bouillon, R.,Munoz, A.,Verstuyf, A.
Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.
Chem.Biol., 15:1029-1034, 2008

PubMed Abstract: Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.

PubMed: 18940664
DOI: 10.1016/j.chembiol.2008.08.008

Experimental method

X-RAY DIFFRACTION (2.7 Å)