Covalent Labeling of Nuclear Vitamin D Receptor with Affinity Labeling Reagents Containing a Cross-linking Probe at Three Different Positions of the Parent Ligand: Structural and Biochemical Implications

Overview

Journal Bioorg Chem

Publisher Elsevier

Specialties Biochemistry
Chemistry

Date 2009 Feb 19

PMID 19223058

Citations 3

Authors

Taner Kaya

Narasimha Swamy

Kelly S Persons

Swapna Ray

Scott C Mohr

Rahul Ray

Affiliations

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Abstract

Structure-functional characterization of vitamin D receptor (VDR) requires identification of structurally distinct areas of VDR-ligand-binding domain (VDR-LBD) important for biological properties of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). We hypothesized that covalent attachment of the ligand into VDR-LBD might alter 'surface structure' of that area influencing biological activity of the ligand. We compared anti-proliferative activity of three affinity alkylating derivatives of 1,25(OH)(2)D(3) containing an alkylating probe at 1,3 and 11 positions. These compounds possessed high-affinity binding for VDR; and affinity labeled VDR-LBD. But, only the analog with probe at 3-position significantly altered growth in keratinocytes, compared with 1,25(OH)(2)D(3). Molecular models of these analogs, docked inside VDR-LBD tentatively identified Ser237 (helix-3: 1,25(OH)(2)D(3)-1-BE), Cys288 (beta-hairpin region: 1,25(OH)(2)D(3)-3-BE,) and Tyr295 (helix-6: 1,25(OH)(2)D(3)-11-BE,) as amino acids that are potentially modified by these reagents. Therefore, we conclude that the beta-hairpin region (modified by 1,25(OH)(2)D(3)-3-BE) is most important for growth inhibition by 1,25(OH)(2)D(3), while helices 3 and 6 are less important for such activity.

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References

Eelen G, Gysemans C, Verlinden L, Vanoirbeek E, De Clercq P, Van Haver D . Mechanism and potential of the growth-inhibitory actions of vitamin D and ana-logs. Curr Med Chem. 2007; 14(17):1893-910. DOI: 10.2174/092986707781058823. View

Rochel N, Wurtz J, Mitschler A, Klaholz B, Moras D . The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000; 5(1):173-9. DOI: 10.1016/s1097-2765(00)80413-x. View

Palomer X, Gonzalez-Clemente J, Blanco-Vaca F, Mauricio D . Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab. 2008; 10(3):185-97. DOI: 10.1111/j.1463-1326.2007.00710.x. View

Ray R, Rose S, Holick S, Holick M . Evaluation of a photolabile derivative of 1,25-dihydroxyvitamin D3 as a photoaffinity probe for 1,25-dihydroxyvitamin-D3 receptor in chick intestinal cytosol. Biochem Biophys Res Commun. 1985; 132(1):198-203. DOI: 10.1016/0006-291x(85)91007-1. View

Vaisanen S, Perakyla M, Karkkainen J, Steinmeyer A, Carlberg C . Critical role of helix 12 of the vitamin D(3) receptor for the partial agonism of carboxylic ester antagonists. J Mol Biol. 2002; 315(2):229-38. DOI: 10.1006/jmbi.2001.5225. View

Swamy N, Persons K, Chen T, Ray R . 1alpha,25-Dihydroxyvitamin D3-3beta-(2)-bromoacetate, an affinity labeling derivative of 1alpha,25-dihydroxyvitamin D3 displays strong antiproliferative and cytotoxic behavior in prostate cancer cells. J Cell Biochem. 2003; 89(5):909-16. DOI: 10.1002/jcb.10585. View

Dalhoff K, Dancey J, Astrup L, Skovsgaard T, Hamberg K, Lofts F . A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer. 2003; 89(2):252-7. PMC: 2394267. DOI: 10.1038/sj.bjc.6601104. View

Johnson C, Muindi J, Hershberger P, Trump D . The antitumor efficacy of calcitriol: preclinical studies. Anticancer Res. 2006; 26(4A):2543-9. View

Lange T, Singh R, Kim K, Zou Y, Kalkunte S, Sholler G . Anti-proliferative and pro-apoptotic properties of 3-bromoacetoxy calcidiol in high-risk neuroblastoma. Chem Biol Drug Des. 2007; 70(4):302-10. PMC: 2519607. DOI: 10.1111/j.1747-0285.2007.00567.x. View

10.

Rochel N, Hourai S, Perez-Garcia X, Rumbo A, Mourino A, Moras D . Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol. Arch Biochem Biophys. 2007; 460(2):172-6. DOI: 10.1016/j.abb.2007.01.031. View

11.

Chen M, Ray S, Swamy N, Holick M, Ray R . Mechanistic studies to evaluate the enhanced antiproliferation of human keratinocytes by 1alpha,25-dihydroxyvitamin D(3)-3-bromoacetate, a covalent modifier of vitamin D receptor, compared to 1alpha,25-dihydroxyvitamin D(3). Arch Biochem Biophys. 1999; 370(1):34-44. DOI: 10.1006/abbi.1999.1353. View

12.

Trump D, Hershberger P, Bernardi R, Ahmed S, Muindi J, Fakih M . Anti-tumor activity of calcitriol: pre-clinical and clinical studies. J Steroid Biochem Mol Biol. 2004; 89-90(1-5):519-26. DOI: 10.1016/j.jsbmb.2004.03.068. View

13.

Nakajima S, Hsieh J, MacDonald P, Haussler C, Galligan M, Jurutka P . Purified human vitamin D receptor overexpressed in E. coli and baculovirus systems does not bind 1,25-dihydroxyvitamin D3 hormone efficiently unless supplemented with a rat liver nuclear extract. Biochem Biophys Res Commun. 1993; 197(2):478-85. DOI: 10.1006/bbrc.1993.2504. View

14.

Bouillon R, Eelen G, Verlinden L, Mathieu C, Carmeliet G, Verstuyf A . Vitamin D and cancer. J Steroid Biochem Mol Biol. 2006; 102(1-5):156-62. DOI: 10.1016/j.jsbmb.2006.09.014. View

15.

Ray R, Holick M . The synthesis of a radiolabeled photoaffinity analog of 1,25-dihydroxyvitamin D3. Steroids. 1988; 51(5-6):623-30. DOI: 10.1016/0039-128x(88)90057-8. View

16.

Wu-Wong J, Tian J, Goltzman D . Vitamin D analogs as therapeutic agents: a clinical study update. Curr Opin Investig Drugs. 2004; 5(3):320-6. View

17.

Sutton A, MacDonald P . Vitamin D: more than a "bone-a-fide" hormone. Mol Endocrinol. 2003; 17(5):777-91. DOI: 10.1210/me.2002-0363. View

18.

Vanhooke J, Tadi B, Benning M, Plum L, Deluca H . New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations. Arch Biochem Biophys. 2007; 460(2):161-5. DOI: 10.1016/j.abb.2006.11.029. View

19.

Jimenez-Lara A, Aranda A . Lysine 246 of the vitamin D receptor is crucial for ligand-dependent interaction with coactivators and transcriptional activity. J Biol Chem. 1999; 274(19):13503-10. DOI: 10.1074/jbc.274.19.13503. View

20.

Swamy N, Xu W, Paz N, Hsieh J, Haussler M, Maalouf G . Molecular modeling, affinity labeling, and site-directed mutagenesis define the key points of interaction between the ligand-binding domain of the vitamin D nuclear receptor and 1 alpha,25-dihydroxyvitamin D3. Biochemistry. 2000; 39(40):12162-71. DOI: 10.1021/bi0002131. View