Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives

Abstract

The secondary bile acid lithocholic acid (LCA) and its derivatives act as selective modulators of the vitamin D receptor (VDR), although their structures fundamentally differ from that of the natural hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3)]. Here, we have determined the crystal structures of the ligand-binding domain of rat VDR (VDR-LBD) in ternary complexes with a synthetic partial peptide of the coactivator MED1 (mediator of RNA polymerase II transcription subunit 1) and four ligands, LCA, 3-keto LCA, LCA acetate, and LCA propionate, with the goal of elucidating their agonistic mechanism. LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR-LBD that 1,25(OH)2D3 binds to, but in the opposite orientation; their A-ring is positioned at the top of the LBP, whereas their acyclic tail is located at the bottom of the LBP. However, most of the hydrophobic and hydrophilic interactions observed in the complex with 1,25(OH)2D3 are reproduced in the complexes with LCA and its derivatives. Additional interactions between VDR-LBD and the C-3 substituents of the A-ring are also observed in the complexes with LCA and its derivatives. These may result in the observed difference in the potency among the LCA-type ligands. The secondary bile acid lithocholic acid (LCA) and its derivatives act as selective modulators of the vitamin D receptor (VDR), although their structures fundamentally differ from that of the natural hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3)]. Here, we have determined the crystal structures of the ligand-binding domain of rat VDR (VDR-LBD) in ternary complexes with a synthetic partial peptide of the coactivator MED1 (mediator of RNA polymerase II transcription subunit 1) and four ligands, LCA, 3-keto LCA, LCA acetate, and LCA propionate, with the goal of elucidating their agonistic mechanism. LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR-LBD that 1,25(OH)2D3 binds to, but in the opposite orientation; their A-ring is positioned at the top of the LBP, whereas their acyclic tail is located at the bottom of the LBP. However, most of the hydrophobic and hydrophilic interactions observed in the complex with 1,25(OH)2D3 are reproduced in the complexes with LCA and its derivatives. Additional interactions between VDR-LBD and the C-3 substituents of the A-ring are also observed in the complexes with LCA and its derivatives. These may result in the observed difference in the potency among the LCA-type ligands. The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], regulates calcium homeostasis (1Haussler M.R. Whitfield G.K. Haussler C.A. Hsieh J.C. Thompson P.D. Selznick S.H. Dominguez C.E. Jurutka P.W. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed.J. Bone Miner. Res. 1998; 13: 325-349Crossref PubMed Scopus (1233) Google Scholar). It also promotes cellular differentiation, inhibits cellular proliferation, and suppresses the immune system (2Abe E. Miyaura C. Sakagami H. Takeda M. Konno K. Yamazaki T. Yoshiki S. Suda T. Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3.Proc. Natl. Acad. Sci. USA. 1981; 78: 4990-4994Crossref PubMed Scopus (1021) Google Scholar, 3DeLuca H.F. Overview of general physiologic features and functions of vitamin D.Am. J. Clin. 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When 1,25(OH)2D3 is bound to VDR, it activates it by inducing conformational changes. The activated complex, VDR/1,25(OH)2D3, binds as a heterodimer with the retinoid X receptor (RXR) to vitamin D response elements located in the promoter region of the target genes. Recruitment of coactivator proteins to this heterodimer is also essential to the transactivation. However, clinical use of 1,25(OH)2D3 is limited because therapeutic doses can give rise to significant hypercalciuria and hypercalcemia (16Bouillon R. Okamura W.H. Norman A.W. Structure-function relationships in the vitamin D endocrine system.Endocr. Rev. 1995; 16: 200-257Crossref PubMed Google Scholar). A number of synthetic ligands to VDR have been developed for medical use; however, most of them can also cause similar problems because they are derived from 1,25(OH)2D3. Several synthetic compounds without the vitamin D3 scaffold have been reported to bind to VDR and have VDR-modulating activities, including growth inhibition of cancer cells and keratinocytes and induction of leukemic cell differentiation, with less calcium mobilization side effects than 1,25(OH)2D3 (17Boehm M.F. Fitzgerald P. Zou A. Elgort M.G. Bischoff E.D. Mere L. Mais D.E. Bissonnette R.P. Heyman R.A. Nadzan A.M. et al.Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3.Chem. Biol. 1999; 6: 265-275Abstract Full Text PDF PubMed Scopus (145) Google Scholar). Therefore, these synthetic compounds are expected to be therapeutics for cancer, leukemia, and psoriasis. Subsequently, Makishima et al. discovered that secondary bile acids, including lithocholic acid (LCA) and its derivatives, also behaved as VDR agonists (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. R. S. K. Masuno H. Shimizu M. K. S. Makishima M. acid derivatives act as selective vitamin D receptor modulators without inducing Res. 49: Full Text Full Text PDF PubMed Scopus Google M. Whitfield G.K. H. Haussler M.R. Vitamin D receptor as bile acid 2002; PubMed Scopus Google Scholar). LCA as a to for and it has been in human and However, the agonistic of LCA as a by VDR because the of LCA is from that of vitamin Additional that VDR functions as a of bile and as endocrine receptor for 1,25(OH)2D3. functions are to cancer C. S. A. and the with nuclear Med. Full Text Full Text PDF PubMed Scopus Google Scholar). to LCA binds to the agonistic of VDR by LCA (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Yamamoto K. T. Makishima M. D. DeLuca H.F. S. between vitamin D receptor and vitamin D Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). we determined the crystal structures of the binding domain of rat VDR in ternary complexes with a synthetic peptide the target of the coactivator MED1 (mediator of RNA polymerase II transcription subunit also as and and the ligands LCA, 3-keto LCA, LCA acetate, and LCA 1) to LCA and its derivatives bind to VDR and they act as the The structures that LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR that 1,25(OH)2D3 binds to A. A. D. of the binding domain of the VDR in complexes with and and Biochem. Biol. 2004; PubMed Scopus Google Scholar, L. P. M. D. R. A. of of 1,25-dihydroxyvitamin D by vitamin D PubMed Scopus Google Scholar, S. T. A. Y. H. D. a the A-ring of 1 alpha,25-dihydroxyvitamin D3 with Med. 49: PubMed Scopus Google Scholar, S. A. A. D. of the vitamin D nuclear receptor binding domain in complex with a side of Biochem. PubMed Scopus Google Scholar, J.M. A. D. The crystal of the nuclear receptor for vitamin D bound to its natural Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. H. M. M. Masuno H. DeLuca H.F. T. D3 biological and crystal Med. 16: PubMed Scopus Google Scholar, J.M. A. D. structures of the vitamin D receptor to Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, J.M. D. structures of the vitamin D nuclear receptor with the vitamin D side and receptor agonists of clinical a for the of to a receptor by side Med. 2004; PubMed Scopus Google M.M. DeLuca H.F. of the rat vitamin D receptor binding domain with vitamin D3 hormone and a coactivator 2004; PubMed Scopus Google but in the opposite of these structures also LCA and its derivatives 1,25(OH)2D3 and give the C-3 substituents on the A-ring the of The structures also a for compounds the scaffold of LCA, 3-keto LCA, and LCA LCA as complex to a of LCA in a of and at and the at for to this and the at for 1 LCA from the with The LCA with and and the The by on with to of LCA The on VDR-LBD and as by et al. and et al. M.M. DeLuca H.F. of the rat vitamin D receptor binding domain with vitamin D3 hormone and a coactivator 2004; PubMed Scopus Google Scholar, M. S. Tanaka T. M. T. Makishima M. H. DeLuca H.F. et structures of rat vitamin D receptor bound to vitamin D for vitamin D receptor and partial Med. PubMed Scopus Google Scholar). The and of the by The of the determined by at with the developed by et al. L. T. to and the of a Sci. 1995; PubMed Scopus Google Scholar). The synthetic which to of rat from of the four ligands, LCA, 3-keto LCA, LCA acetate, and LCA propionate, used to a ternary complex of in and the ternary complexes at in a of and The with for the ternary complexes at at at the of the and and with The for complex is the cell are in 1 with complex The structures by molecular by the crystal of the ternary complex reported by et al. as the in M.M. DeLuca H.F. of the rat vitamin D receptor binding domain with vitamin D3 hormone and a coactivator 2004; PubMed Scopus Google Scholar, P.D. P. J. M. et a for D Biol. 1998; PubMed Scopus Google Scholar). with and D.E. for and Biol. 1999; PubMed Scopus Google and cell of in a The crystal structures of the ternary complexes of VDR-LBD with LCA and its derivatives determined at by 1 and Most of the in the complexes however, the region the region and and the of and and of the MED1 peptide to in these at the and also in the complexes with LCA and 3-keto Most of these reported as in of other ternary complexes of VDR and are a to of VDR complexes A. A. D. of the binding domain of the VDR in complexes with and and Biochem. Biol. 2004; PubMed Scopus Google Scholar, L. P. M. D. R. A. of of 1,25-dihydroxyvitamin D by vitamin D PubMed Scopus Google Scholar, S. T. A. Y. H. D. a the A-ring of 1 alpha,25-dihydroxyvitamin D3 with Med. 49: PubMed Scopus Google Scholar, S. A. A. D. of the vitamin D nuclear receptor binding domain in complex with a side of Biochem. PubMed Scopus Google Scholar, J.M. A. D. The crystal of the nuclear receptor for vitamin D bound to its natural Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. H. M. M. Masuno H. DeLuca H.F. T. D3 biological and crystal Med. 16: PubMed Scopus Google Scholar, J.M. A. D. structures of the vitamin D receptor to Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, J.M. D. structures of the vitamin D nuclear receptor with the vitamin D side and receptor agonists of clinical a for the of to a receptor by side Med. 2004; PubMed Scopus Google M.M. DeLuca H.F. of the rat vitamin D receptor binding domain with vitamin D3 hormone and a coactivator 2004; PubMed Scopus Google Scholar). The structures of VDR-LBD in the four complexes are The between the proteins in the LCA complex and of the 3-keto LCA, LCA acetate, and LCA complexes are and the of and the between the proteins in the LCA and 1,25(OH)2D3 complexes is for the Therefore, significant among the proteins in the ternary complexes with LCA, its derivatives, 1,25(OH)2D3 M. Y. H. M. M. Masuno H. DeLuca H.F. T. D3 biological and crystal Med. 16: PubMed Scopus Google Scholar, M.M. DeLuca H.F. of the rat vitamin D receptor binding domain with vitamin D3 hormone and a coactivator 2004; PubMed Scopus Google Scholar). in the super family have a ligand-binding pocket in and and and the for the of The natural hormone 1,25(OH)2D3 is in the LBP. the we observed in the LBP, as reported in the complex with 1,25(OH)2D3 M. Y. H. M. M. Masuno H. DeLuca H.F. T. D3 biological and crystal Med. 16: PubMed Scopus Google and of the of LCA and its derivatives in the complex for their LCA and its derivatives are in the of VDR-LBD with However, their is opposite to that of 1,25(OH)2D3 in the and The is the and the of the is in the bottom of the LBP, the A-ring LCA at the of the with the in the side of in 1 between the of the and the is and in between the of the and the is The other of the same a between the of the and the is with the in the side of in and the in the side of in between the and these are and These are also observed in the other The four of the in of the complexes with hydrophobic in the hydrophobic are and from the hydrophobic interactions are also in the other between VDR and the ligands are also observed at the other of the ligands, the C-3 of the The four ligands differ in their substituents at this The of LCA, the of 3-keto LCA, the of LCA propionate, and the of LCA with in and the complexes with LCA and 3-keto LCA, the of the and of the substituents a with the of of in and in in the complex with LCA acetate, the of the a with the of the of the complex with LCA propionate, the of the also a with the of the of the of the substituents with the of in and in and with the side of and in the binding of the derivatives to the of VDR-LBD this LCA may be the most of the four ligands because it has the in the super family proteins for of a and a The domain of the VDR-LBD of and and and it with the as the the we a peptide the target of the MED1 coactivator and determined the of the peptide in the four ternary complexes to LCA and its derivatives coactivator The peptide binds to the domain in of the four complexes similar to the complex with 1,25(OH)2D3. of the and have as the of the peptide with a at in complex The of the peptide in the four complexes is The between the in the LCA complex and the 3-keto LCA, LCA acetate, and LCA complexes are and the of The of the peptide in the LCA complex also with that in the 1,25(OH)2D3 The between the at significant among the in the ternary complexes with LCA, its derivatives, and 1,25(OH)2D3 M. Y. H. M. M. Masuno H. DeLuca H.F. T. D3 biological and crystal Med. 16: PubMed Scopus Google Scholar, M.M. DeLuca H.F. of the rat vitamin D receptor binding domain with vitamin D3 hormone and a coactivator 2004; PubMed Scopus Google Scholar). The domain a of hydrophobic in in in in and in The peptide binds to this the hydrophobic interactions between the of the peptide and the of the The side of in and in also the binding of the peptide by it on the of the domain are between the of the side of and the of and the of the side of and the of these interactions observed in the are the same as in the complex with 1,25(OH)2D3. Therefore, these that the interactions between the coactivator MED1 and the domain are in the ternary complexes with LCA and its derivatives. the of its as of VDR, LCA has been expected to be used a vitamin D because LCA to VDR without However, because the of LCA LCA derivatives with activities have been by and the we determined the structures of ternary complexes of VDR-LBD with LCA and its derivatives and they bind to LCA and its derivatives bind to the same that 1,25(OH)2D3 binds However, their is opposite to that of 1,25(OH)2D3 A-ring on the of the LBP, its the LBP. this is the same as that of acid in the X receptor S. J.M. R. S. for bile acid binding and of the nuclear receptor Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). LCA and its derivatives are similar in to natural 1,25(OH)2D3 and although their are the of the scaffold of LCA the of the of 1,25(OH)2D3 the to be to the agonistic of a ligands a conformational of to the active which is by hydrophobic interactions between the and and and of rat VDR, the and the coactivator to which is for the VDR ligands with and the active ligands have been reported to of agonistic M. S. Tanaka T. M. T. Makishima M. H. DeLuca H.F. et structures of rat vitamin D receptor bound to vitamin D for vitamin D receptor and partial Med. PubMed Scopus Google Scholar, Y. M. T. T. Shimizu M. Yamamoto K. of vitamin D receptor agonistic Biochem. Biol. PubMed Scopus Google Scholar). their opposite LCA and its derivatives can the interactions between VDR and which of a hydrophobic and The are located at the of the and binding the hydrophobic the hydrophobic of the LBP. the complex with the A-ring of 1,25(OH)2D3 the and its is on the of the LBP. are at the and C-3 of the A-ring of of with the side of and and and the of 1,25(OH)2D3 also a with the of the of and LCA and its derivatives of the hydrophobic and at the However, they most of the between the and the by the between the A-ring and the of the with the of a of with the side of and and with and The with the of the of and are on the substituents at the C-3 of the Therefore, the between the and the is the same for LCA and their are et al. also the of the for agonistic by that of the of LCA its agonistic (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). LCA the and properties of 1,25(OH)2D3 as its is than 1,25(OH)2D3. a binding VDR to as and for 1,25(OH)2D3 and LCA, M. M. R. S. K. Masuno H. Shimizu M. K. S. Makishima M. acid derivatives act as selective vitamin D receptor modulators without inducing Res. 49: Full Text Full Text PDF PubMed Scopus Google Scholar). the of the hydrophobic of LCA and 1,25(OH)2D3 are and the hydrophobic of LCA with VDR be expected to be than that of 1,25(OH)2D3. the difference of the between LCA and 1,25(OH)2D3 that the LCA a to the of of the is in the the is in the the C-3 of the A-ring in the complex with However, the the interactions mediated by to be less for the complex than the hydrophobic The substituents at the C-3 of the A-ring of LCA also the of human VDR, and LCA and LCA are agonists than LCA and 3-keto LCA (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. R. S. K. Masuno H. Shimizu M. K. S. Makishima M. acid derivatives act as selective vitamin D receptor modulators without inducing Res. 49: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Yamamoto K. T. Makishima M. D. DeLuca H.F. S. between vitamin D receptor and vitamin D Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. A. C. A. M. R. K. R. J. and selective bile acid derivatives as biological and molecular Med. PubMed Scopus Google Scholar). The that for LCA and LCA are than LCA M. M. R. S. K. Masuno H. Shimizu M. K. S. Makishima M. acid derivatives act as selective vitamin D receptor modulators without inducing Res. 49: Full Text Full Text PDF PubMed Scopus Google Scholar). LCA is than LCA whereas 3-keto LCA is to LCA (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). crystal structures that the C-3 substituents of the derivatives with VDR a the a to with the of these with the hydrophobic of VDR, including and and of rat VDR, which are in the VDR These interactions are the for the potency of these ligands because this is in the with the ligands in the of LCA and 3-keto These interactions at the C-3 may also of the the human and to and of rat VDR, the of LCA, whereas they activated by LCA (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). The interactions at the C-3 for the of the to the to of the other from the also be from (18Adachi R. Honma Y. Masuno H. Kawana K. Shimomura I. S. Makishima M. of vitamin D receptor by lithocholic acid acetate, a bile acid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. R. S. K. Masuno H. Shimizu M. K. S. Makishima M. acid derivatives act as selective vitamin D receptor modulators without inducing Res. 49: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Yamamoto K. T. Makishima M. D. DeLuca H.F. S. between vitamin D receptor and vitamin D Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. A. C. A. M. R. K. R. J. and selective bile acid derivatives as biological and molecular Med. PubMed Scopus Google Scholar). The of rat can to LCA but to 1,25(OH)2D3. The is with the A-ring of 1,25(OH)2D3 a and the to the of the but also the the other the A-ring is by a in LCA to in the the of rat is activated by 1,25(OH)2D3 but by The side of the also with the of the A-ring of 1,25(OH)2D3 and the of The to the but there is to the side in LCA the that the hydrophobic to the of the The role of of rat in the interactions with the ligands LCA and 3-keto LCA with in a similar the of rat the LCA but has on by LCA 3-keto The to the A-ring of LCA, It is also in the and 3-keto These interactions are the interactions between the and and the to may a conformational of the which the to the LCA activates VDR, it functions from for it The most difference in the binding between 1,25(OH)2D3 and the ligands reported are the of the with in and in of 1,25(OH)2D3 the with these the ligands a to with which is to the with the A-ring of 1,25(OH)2D3 with a to the hydrophobic interactions as by the These may the of the the interactions between VDR and the However, we significant in the interactions between VDR and the coactivator is the crystal The coactivator peptide with VDR but also role in the crystal and be in its active at as in the conditions M. S. Tanaka T. M. T. Makishima M. H. DeLuca H.F. et structures of rat vitamin D receptor bound to vitamin D for vitamin D receptor and partial Med. PubMed Scopus Google Scholar). the that may be by LCA have been by the crystal The that LCA from 1,25(OH)2D3 a also be cellular be in the the for the difference in the agonistic between the ligands, it be to the The crystal structures reported have the and between ligands and 1,25(OH)2D3 in their interactions with VDR and a for the of ligands on LCA, with The of the determined structures have been in the with and for the LCA, LCA acetate, and LCA The H. and H. of and for this The also the at the of the for of the ligand-binding domain ligand-binding pocket lithocholic acid of RNA polymerase II transcription subunit 1 nuclear receptor 1α,25-dihydroxyvitamin D3 retinoid X receptor vitamin D receptor