New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model.

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Research Abstract Details 

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New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Abstract Text:

Mathew T Mizwicki,Craig M Bula,June E Bishop,Anthony W Norman,

Recently, we have developed a Vitamin D sterol (VDS)-VDR conformational ensemble model. This model can be broken down into three individual, yet interlinked parts: (a) the conformationally flexible VDS, (b) the apo/holo-VDR helix-12 (H12) conformational ensemble, and (c) the presence of two VDR ligand binding pockets (LBPs); one thermodynamically favored (the genomic pocket, G-pocket) and the other kinetically favored by VDSs (the alternative pocket, A-pocket). One focus of this study is to use directed VDR mutagenesis to (1) demonstrate H12 is stabilized in the transcriptionally active closed conformation (hVDR-c1) by three salt-bridges that span the length of H12 (cationic residues R154, K264 and R402), (2) to elucidate the VDR trypsin sites [R173 (hVDR-c1), K413 (hVDR-c2) and R402 (hVDR-c3)] and (3) demonstrate the apo-VDR H12 equilibrium can be shifted. The other focus of this study is to apply the model to generate a mechanistic understanding to discrepancies observed in structure-function data obtained with a variety of 1alpha,25(OH)(2)-Vitamin D(3) (1,25D) A-ring and side-chain analogs, and side-chain metabolites. We will demonstrate that these structure-function conundrums can be rationalized, for the most part by focusing on alterations in the VDS conformational flexibility and the elementary interaction between the VDS and the VDR A- and G-pockets, relative to the control, 1,25D.

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Publishing Authors By Initials

MT Mizwicki,CM Bula,JE Bishop,AW Norman,

For similar polycyclic compounds: steroids: secosteroids: vitamin d research abstracts see: polycyclic compounds: steroids: secosteroids: vitamin d research

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New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of steroid biochemistry and molecular

VOLUME: 103

Page Numbers: 243-62

Journal Abbreviation: J. Steroid Biochem. Mol. Biol.

ISSN: 0960-0760

DAY: 3

MONTH: Mar

YEAR: 2007

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9015483

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Keywords Mesh Terms:

KEYWORDS: Vitamin D

MESH TERMS: metabolism

Chemical & Substance for Abstract: New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. Information

Substance Name: Trypsin

Registry Number: EC 3.4.21.4

Grant and Affiliation Information for New insights into Vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model.

AFFILIATION: Department of Biochemistry, University of California-Riverside, Riverside, CA 92521, USA.

Country: England

AGENCY: United States NIDDK

GRANT: R01 DK009012-39A1

ACRONYM: DK

MEDLINETA: J Steroid Biochem Mol Biol

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