Three-dimensional model of the ligand binding domain of the nuclear receptor for 1α,25-dihydroxy-vitamin D3

✍ Scribed by Anthony W. Norman; Derk Adams; Elaine D. Collins; William H. Okamura; Robert J. Fletterick

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 449 KB
• Volume: 74
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/(sici)1097-4644(19990901)74:3<323::aid-jcb2>3.0.co;2-v

✦ Synopsis

A three-dimensional model for residues 142-427 of the ligand binding domain (LBD) of the human nuclear receptor for 1␣,25-dihydroxy-vitamin D 3 [VDR] has been generated based on the X-ray crystallographic atomic coordinates of the LBD of the rat ␣1 thyroid receptor (TR). The VDR LBD model is an elongated globular shape comprised of an antiparallel ␣-helical triple sandwich topology, made up of 12 ␣-helical elements linked by short loop structures; collectively these structural features are similar to the characteristic secondary and tertiary structures for six nuclear receptors with known X-ray structures. The model has been used to describe the interaction of the conformationally flexible natural hormone, 1␣,25-dihydroxy-vitamin D 3 [1␣,25(OH) 2 D 3 ], and a number of related analogs with the VDR LBD. The optimal orientation of the 1␣,25(OH) 2 D 3 in the LBD is with its A-ring directed towards the interior and its flexible side chain pointing towards and interacting with helix-12, site of the activation function-2 domain (AF-2) of the VDR. Mapping of four natural and one experimental point mutations of the VDR LBD, which result in ligand-related receptor dysfunction, indicates the close proximity of these amino acids to the bound ligand.