Probing a Water Channel near the A-Ring of Receptor-Bound 1,25-Dihydroxyvitamin D3 with Selected 2
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- 作者：Shinji Hourai ; Toshie Fujishima ; Atsushi Kittaka ; Yoshitomo Suhara ; Hiroaki Takayama ; Natacha Rochel ; Dino Moras
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：August 24, 2006
- 年：2006
- 卷：49
- 期：17
- 页码：5199 - 5205
- 全文大小：376K
- 年卷期：v.49,no.17(August 24, 2006)
- ISSN：1520-4804
文摘
The crystal structure of the vitamin D receptor (VDR) in complex with 1
,25(OH)2D3 revealed the presenceof several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, wereport the crystal structures of the human VDR ligand binding domain bound to selected C-2 substitutedanalogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacementsdo not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, allanalogues affect the presence and/or the location of the above water molecules. The integrity of the channelinteractions and specific C-2 analogue directed additional interactions correlate with the binding affinityof the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 celldifferentiation. Our overall findings highlight a rational approach to the design of more potent ligands bybuilding in features revealed in the crystal structures.
,25(OH)2D3 revealed the presenceof several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, wereport the crystal structures of the human VDR ligand binding domain bound to selected C-2 substitutedanalogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacementsdo not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, allanalogues affect the presence and/or the location of the above water molecules. The integrity of the channelinteractions and specific C-2 analogue directed additional interactions correlate with the binding affinityof the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 celldifferentiation. Our overall findings highlight a rational approach to the design of more potent ligands bybuilding in features revealed in the crystal structures.