کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9895216 | 1542747 | 2005 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Applications of the Vitamin D sterol-Vitamin D receptor (VDR) conformational ensemble model
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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![عکس صفحه اول مقاله: Applications of the Vitamin D sterol-Vitamin D receptor (VDR) conformational ensemble model Applications of the Vitamin D sterol-Vitamin D receptor (VDR) conformational ensemble model](/preview/png/9895216.png)
چکیده انگلیسی
Over the past 20 years much has been learned about the cellular actions of the steroid hormone 1α,25(OH)2-Vitamin D3 (1,25D). Perhaps most importantly structure-function studies led to the discovery that different chemical and physical features of 1,25D are preferred to initiate either exonuclear, non-genomic or endonuclear, genomic cellular signaling. It is well documented that both a 1α-OH and 25-OH, and a 6-s-trans, bowl-shaped, sterol conformation are absolutely required for efficient gene transcription, while 6-s-cis locked analogs and 1-deoxy, 25(OH)D3 metabolites activate a variety of non-genomic, rapid responses. These results and the observation that S237 (helix-3; H3) and R274 (H5) are the most static residues in the human 1,25D-Vitamin D receptor (VDR) X-ray construct (see B-values in pdb: 1DB1) and form H-bonds with the 1α-OH of 1,25D in the X-ray, genomic pocket (G-pocket), provided the basis for the molecular modeling experiments that led to the discovery of a putative VDR alternative ligand binding pocket (A-pocket). The conformational ensemble model generated from the in silico results provides an explanation for how the VDR can function as a receptor propagating both genomic and non-genomic signaling events. In this report the theoretical gating properties controlling ligand access to the A- and G-pockets will be compared and the model will be used to provide a molecular explanation for the confusing structure-function results pertaining to 1,25D, its side-chain metabolite, 23S,25R-1α,25(OH)2-D3-26,23-lactone (BS), and its synthetic two side-chain analog, 21-(3â²-hydroxy-3â²-methylbutyl)-1α,25(OH)2-D3 (KH or Gemini). In addition, evidence that the model is consistent with the pH requirement for Vitamin D sterol-VDR crystallization will be presented.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Steroids - Volume 70, Issues 5â7, MayâJune 2005, Pages 464-471
Journal: Steroids - Volume 70, Issues 5â7, MayâJune 2005, Pages 464-471
نویسندگان
Mathew T. Mizwicki, June E. Bishop, Anthony W. Norman,