Nuclear receptor for 1&agr;,25-dihydroxyvitamin D3 useful...

Data processing: structural design – modeling – simulation – and em – Simulating nonelectrical device or system – Biological or biochemical

Reexamination Certificate

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C703S002000, C703S012000, C702S027000, C434S277000, C434S278000, C556S467000

Reexamination Certificate

active

06516294

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of Invention
This invention concerns the nuclear receptor for the steroid hormone 1&agr;,25-dihydroxyvitamin D
3
, its ligand binding domain three-dimensional model thereof and a method for selection of suitable vitamin D
3
binding to the 1&agr;,25-dihydroxyvitamin D
3
receptor. In particular, the invention concerns a three-dimensional model for residues 142-427 of the ligand binding domain of the human nuclear receptor for 1&agr;,25-dihydroxyvitamin D
3
used to identify the interaction of the conformationally flexible natural hormone 1&agr;,25(OH)
2
D
3
and a number of related analogs with the receptor ligand binding domain. The optimal orientation of the model provides a generally useful method for identification and generation of new potential analog drug forms of dihydroxyvitamin D
3
.
2. Background Art and Related Disclosures
The receptors for all of the steroid hormones, such as 1&agr;,25-dihydroxyvitamin D
3
, thyroid hormone, retinoic acid, triodothyronine, estradiol, cortisol, androgen and others are proteins that exist either exclusively in the cell nucleus or are partitioned between the cytoplasm and nucleus. Typically, the steroid receptor contain DNA binding domain at its 5′ end and the ligand binding domain at its 3′ end. The ligand is either the steroid hormone or steroid vitamin.
These nuclear proteins receptors specifically bind physiologically important molecules, namely their corresponding steroid hormones and vitamins.
Steroid hormones, which include 1,25-dihydroxyvitamin D
3
, generate biological responses primarily by stimulating the synthesis of mRNA at the level of the initiation of gene transcription.
The binding of ligands to nuclear receptors leads to conformational changes in the receptor (
J. Biol. Chem.,
270: 10551 (1995)), that promote formation of heterodimers with the retinoid X receptor (
Mol. Endocrinol.,
10: 1617 (1995) and enhance binding to DNA coactivators (
Mol. Endocrinol.,
5: 1815 (1991), and transcriptional activation (
Genes and Development,
12: 1787 (1998).
As described above, binding of the cognate ligands to the nuclear receptors leads to conformational changes in the receptor that promote formation of heterodimers with the retinoid X receptor (RXR), and thereby enhance binding to DNA coactivators, which result in effective transcriptional activation, that is to a stimulation of gene transcription with the appearance of new messenger RNAs coding for proteins related to the ultimate biological response.
The three-dimensional x-ray structure for six nuclear receptors has been previously determined. These include the thyroid hormone receptor (TR), retinoic acid receptor (RAR), the estrogen receptor (ER), the progesterone receptor (PR) and the ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor (PPAR). These structures have all been determined with their respective bound ligands. For the ER LBD, an x-ray structure is also known with the bound ligand raloxifene, a tissue-specific antagonist of the transcriptional activation function of the ligand-receptor complex. The x-ray structure is known for the LBD of the unoccupied 9-cis retinoic acid receptor.
While the structural aspects of all six protein LBDs were found to be remarkably similar with respect to their basic secondary and tertiary structural elements, details of the interior surface of the LBD which directly interacts with the appropriate cognate ligand are different for all receptors.
Nuclear receptor ligands and ligand binding domains, particularly that of thyroid receptor are disclosed in the PCT application PCT/US/96/20778, filed on Dec. 13, 1996, incorporated by reference. Selective thyroid hormone analogs are disclosed in U.S. Pat. No. 5,883,294, incorporated by reference. In vitro method of evaluating the antagonistic and agonistic effect of receptor-binding ligands is disclosed in the U.S. Pat. No. 5,578,445, incorporated by reference.
Vitamin D
3
analogs and their therapeutic utility is disclosed in the copending application Ser. No. 09/074,565, filed on May 6, 1998 and Ser. No. 09/073,723, filed on May 6, 1998, both incorporated by reference.
Vitamin D
3
(1&agr;,25 dihydroxyvitamin D
3
) belongs to the family of steroid receptors. However, its three-dimensional x-ray structure has not been previously determined.
It is, therefore, a primary objective of this invention to describe a three-dimensional x-ray structure model for ligand binding domain of the human nuclear receptor and its optimal orientation permitting identification and generation of pharmacologically active vitamin D
3
ligands.
All cited patents, patent applications and publication are hereby incorporated by reference.
SUMMARY
One aspect of the current invention is a three-dimensional model for residues 142-427 of the ligand binding domain of the human nuclear receptor for 1&agr;,25-dihydroxyvitamin D
3
.
Another aspect of the current invention is a method for selection of suitable vitamin D
3
analogs and ligands binding to the 1&agr;,25-dihydroxyvitamin D
3
receptors.
Still another aspect of the current invention is a three dimensional x-ray structure model of the nuclear receptor for 1&agr;,25-dihydroxyvitamin D
3
.
Definitions
As defined herein:
“1&agr;,25(OH)
2
D
3
” or “vitamin D
3
” means 1&agr;,25-dihydroxyvitamin D
3
.
“VDR LBD” means ligand binding domain of the vitamin D
3
receptor.
“LBD” means ligand binding domain.
“VDR” means vitamin D
3
receptor.
“ER” means estrogen receptor.
“TR” means thyroid receptor.
“RAR” means retinoic acid receptor.


REFERENCES:
patent: 5883294 (1999-03-01), Scanlan et al.
patent: WO/93/07290 (1993-04-01), None
patent: WO/97/21993 (1997-06-01), None
Yamamoto et al. Conformationally restricted analogs of 1a-25-dihydroxyvitamin D3 and its 20-epimer: compounds for study of the three-dimensional structure of vitamin D responsible for binding to the receptor. J. Med. Chem, vol. 39, pp. 2727-2737, 1996.*
Liu et al. Differential interaction of 1a,25-dihydroxyvitamin D3 analogues and their 20-epi homologues with the vitamin D receptor. J. Biol. Chem., vol. 272, pp. 3336-3345, 1997.*
Andrzej M. Brzozowski et al., Molecular Basis of Agonism and Antagonism in the Oestrogen Receptor,Nature, 389:753-758, (Oct. 16, 1997).
Richard L. Wagner, et al. A Structural Role for Hormone in the Thyroid Hormone Receptor,Nature, 378:690-697 (Dec. 14, 1995).

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