Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands

被引:203
作者
Tocchini-Valentini, G [1 ]
Rochel, N [1 ]
Wurtz, JM [1 ]
Mitschler, A [1 ]
Moras, D [1 ]
机构
[1] Univ Strasbourg 1, Lab Biol & Genom Struct, Unite Propre Rech 9004, Inst Genet & Biol Mol & Cellulaire,CNRS,INSERM, F-67404 Illkirch, France
关键词
20-epi analogs; nuclear receptors; VDR;
D O I
10.1073/pnas.091018698
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The crystal structures of the ligand-binding domain (LBD) of the vitamin D receptor complexed to 1 alpha ,25(OH)(2)D-3 and the 20-epi analogs, MC1288 and KH1060, show that the protein conformation is identical, conferring a general character to the observation first made for retinoic acid receptor (RAR) that, for a given LED, the agonist conformation is unique, the ligands adapting to the binding pocket. In all complexes, the A- to D-ring moieties of the ligands adopt the same conformation and form identical contacts with the protein. Differences are observed only for the 17 beta -aliphatic chains that adapt their conformation to anchor the 25-hydroxyl group to His-305 and His-397. The inverted geometry of the C20 methyl group induces different paths of the aliphatic chains. The ligands exhibit a low-energy conformation for MC1288 and a more strained conformation for the two others. KH1060 compensates this energy cost by additional contacts. Based on the present data, the explanation of the superagonist effect is to he found in higher stability and longer half-life of the active complex, thereby excluding different conformations of the ligand binding domain.
引用
收藏
页码:5491 / 5496
页数:6
相关论文
共 31 条
[1]   STRUCTURE-FUNCTION-RELATIONSHIPS IN THE VITAMIN-D ENDOCRINE SYSTEM [J].
BOUILLON, R ;
OKAMURA, WH ;
NORMAN, AW .
ENDOCRINE REVIEWS, 1995, 16 (02) :200-257
[2]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[3]   Annealing in crystallography: a powerful optimization tool [J].
Brunger, AT ;
Adams, PD ;
Rice, LM .
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, 1999, 72 (02) :135-155
[4]  
DeLuca HF, 1998, NUTR REV, V56, pS4
[5]   The vitamin D analog, KH1060, is rapidly degraded both in vivo and in vitro via several pathways: Principal metabolites generated retain significant biological activity [J].
Dilworth, FJ ;
Williams, GR ;
Kissmeyer, AM ;
Nielsen, JL ;
Binderup, E ;
Calverley, MJ ;
Makin, HLJ ;
Jones, G .
ENDOCRINOLOGY, 1997, 138 (12) :5485-5496
[6]   Ligand-protein interactions in nuclear receptors of hormones [J].
Egea, PF ;
Klaholz, BP ;
Moras, D .
FEBS LETTERS, 2000, 476 (1-2) :62-67
[7]   IMPROVED METHODS FOR BUILDING PROTEIN MODELS IN ELECTRON-DENSITY MAPS AND THE LOCATION OF ERRORS IN THESE MODELS [J].
JONES, TA ;
ZOU, JY ;
COWAN, SW ;
KJELDGAARD, M .
ACTA CRYSTALLOGRAPHICA SECTION A, 1991, 47 :110-119
[8]   Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARγ [J].
Klaholz, BP ;
Mitschler, A ;
Belema, M ;
Zusi, C ;
Moras, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (12) :6322-6327
[9]   Conformational adaptation of agonists to the human nuclear receptor RARγ [J].
Klaholz, BP ;
Renaud, JP ;
Mitschler, A ;
Zusi, C ;
Chambon, P ;
Gronemeyer, H ;
Moras, D .
NATURE STRUCTURAL BIOLOGY, 1998, 5 (03) :199-202
[10]   Structural basis for isotype selectivity of the human retinoic acid nuclear receptor [J].
Klaholz, BP ;
Mitschler, A ;
Moras, D .
JOURNAL OF MOLECULAR BIOLOGY, 2000, 302 (01) :155-170