Vitamin D Analogs Bearing C-20 Modifications Stabilize the Agonistic Conformation of Non-Responsive Vitamin D Receptor Variants

被引：4

作者：

Belorusova, Anna Y. ^{[1
,2
,3
,4
,7
]}

Rovito, Daniela ^{[1
,2
,3
,4
,5
]}

Chebaro, Yassmine ^{[1
,2
,3
,4
]}

Doms, Stefanie ^{[6
]}

Verlinden, Lieve ^{[6
]}

Verstuyf, Annemieke ^{[6
]}

Metzger, Daniel ^{[1
,2
,3
,4
,5
]}

Rochel, Natacha ^{[1
,2
,3
,4
]}

Laverny, Gilles ^{[1
,2
,3
,4
,5
]}

机构：

[1] Inst Genet & Biol Mol & Cellulaire IGBMC, F-67400 Illkirch Graffenstaden, France

[2] Ctr Natl Rech Sci CNRS, UMR 7104, F-67400 Illkirch Graffenstaden, France

[3] Inst Natl Sante & Rech Med INSERM, UMR S 1258, F-67400 Illkirch Graffenstaden, France

[4] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire IGBMC, INSERM U1258, CNRS UMR 7104, F-67404 Illkirch Graffenstaden, France

[5] OSCAR, French Network Rare Bone Dis, F-94270 Le Kremlin Bicetre, France

[6] Katholieke Univ Leuven, Dept Chron Dis & Metab, Clin & Expt Endocrinol, B-3000 Leuven, Belgium

[7] Zobio BV, Dept Assay Dev & Screening, NL-2333 CH Leiden, Netherlands

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2022年 / 23卷 / 15期

关键词：

structure function relationship; vitamin D; rare diseases; D-RESISTANT RICKETS; D NUCLEAR RECEPTOR; TRANSCRIPTIONAL ACTIVATION; LIGAND; BINDING; GEMINI; POTENT; MUTATION;

D O I：

10.3390/ijms23158445

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Vitamin D receptor (VDR) plays a key role in calcium homeostasis, as well as in cell proliferation and differentiation. Among the large number of VDR ligands that have been developed, we have previously shown that BXL-62 and Gemini-72, two C-20-modified vitamin D analogs are highly potent VDR agonists. In this study, we show that both VDR ligands restore the transcriptional activities of VDR variants unresponsive to the natural ligand and identified in patients with rickets. The elucidated mechanisms of action underlying the activities of these C-20-modified analogs emphasize the mutual adaptation of the ligand and the VDR ligand-binding pocket.

引用

页数：11

共 36 条

[1] Single-cell analyses unravel cell type-specific responses to a vitamin D analog in prostatic precancerous lesions [J].

Abu el Maaty, Mohamed A. ;

Grelet, Elise ;

Keime, Celine ;

Rerra, Anna-Isavella ;

Gantzer, Justine ;

Emprou, Camille ;

Terzic, Julie ;

Lutzing, Regis ;

Bornert, Jean-Marc ;

Laverny, Gilles ;

Metzger, Daniel .

SCIENCE ADVANCES, 2021, 7 (31)

[2] A robust bulk-solvent correction and anisotropic scaling procedure [J].

Afonine, PV ;

Grosse-Kunstleve, RW ;

Adams, PD .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2005, 61 :850-855

[3] Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D [J].

Belorusova, Anna Y. ;

Suh, Nanjoo ;

Lee, Hong Jin ;

So, Jae Young ;

Maehr, Hubert ;

Rochel, Natacha .

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2017, 173 :69-74

[4] Structural Studies of Vitamin D Nuclear Receptor Ligand-Binding Properties [J].

Belorusova, Anna Y. ;

Rochel, Natacha .

VITAMIN D HORMONE, 2016, 100 :83-116

[5] New aspects of vitamin D metabolism and action - addressing the skin as source and target [J].

Bikle, Daniel ;

Christakos, Sylvia .

NATURE REVIEWS ENDOCRINOLOGY, 2020, 16 (04) :234-252

[6]

Bricogne G., 2011, BUSTER VERSION 2 10

[7] Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: Remodelling the LBP with one side chain rotation [J].

Ciesielski, Fabrice ;

Rochel, Natacha ;

Moras, Dino .

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2007, 103 (3-5) :235-242

[8] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

[9] Scaling and assessment of data quality [J].

Evans, P .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2006, 62 :72-82

[10]

Feldman David, 2014, Bonekey Rep, V3, P510, DOI 10.1038/bonekey.2014.5

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