STRUCTURE/FUNCTION STUDIES OF VITAMIN D BINDING PROTEIN
STRUCTURE/FUNCTION STUDIES OF VITAMIN D BINDING PROTEIN
批准号:
6177137
负责人:
RAHUL RAY
金额:
$16.52万
依托单位国家:
美国
项目类别:
财政年份:
1993
资助国家:
美国
项目状态:
已结题
起止时间:
1993-01-01 至 2002-04-30
关键词:
1,25 dihydroxycholecalciferol 25 hydroxycholecalciferol X ray crystallography affinity labeling chemical binding fatty acid binding protein hormone binding protein hormone regulation /control mechanism macrophage activating factor molecular site osteoclast activating factor point mutation protein sequence protein structure function vitamin D vitamin analog
中文摘要
描述(摘自申请者的摘要):维生素D结合
蛋白质(DBP)与维生素D及其代谢产物以及G-肌动蛋白结合
高亲和力,并用于将前者输送到靶组织,并
清除后者,以防止其在细胞损伤过程中聚合。
DBP还与脂肪酸结合,并增强中性粒细胞上的补体激活
通过与C5a Des Arg结合而趋化。此外,众所周知,DBP是
体内转化为强大的巨噬细胞和破骨细胞激活因子
(DBP-MAF)。
这项建议的目标是研究各种结构-功能
使用多种方法的DBP和DBP-MAF的各个方面,包括
维生素D、甾醇和脂肪酸结合域的化学修饰
通过亲和/光亲和标记DBP,操纵DBP-基因以
表达DBP突变体和片段及其功能特性,
X射线测定DBP及DBP-肌动蛋白复合体的三维结构
结晶学、巨噬细胞超氧化物生成和骨吸收
化验(DBP-MAF活性)。
DBP的多任务特性直接与特定的
DBP对各种配体的识别/结合。这样的过程是强烈的
受蛋白质结构,特别是三维结构的影响
负责这种识别和识别的蛋白质结构域
有约束力的。因此,这些研究将提供有关重要性的信息
在DBP的多域结构中的独立结构域,可能
各种内源配体共用一个共同的结合口袋,程度
不同领域之间的串扰,不同配体之间的相互依赖,以及
配体结合对DBP-MAF活性的影响。
DBP在1,25(OH)2D3的代谢活化中起着至关重要的作用。
促钙激素及其组织特异性递送,使后者
可负责钙磷的动态平衡、调节
细胞的生长和成熟,恶性细胞的抗增殖,以及
免疫调节。DBP与G-肌动蛋白的相互作用在
细胞过程中肌动蛋白聚合和动脉阻塞的预防
受伤。另一方面,DBP-MAF对巨噬细胞的激活也强调了
DBP可能的免疫调节作用。此外,
破骨细胞激活(通过DBP-MAF)增加了这一可能性
细胞因子可能参与炎症性关节疾病,如
骨关节炎、类风湿性关节炎、牙周病等
建议的结构-功能研究应该在评估方面有价值
DBP和DBP的多种功能及其可能的生理意义
DBP-MAF。
英文摘要
DESCRIPTION (Adapted from the Applicant's Abstract): Vitamin D-binding
protein (DBP) binds vitamin D and its metabolites as well as G-actin with
high affinity and serves to transport the former to target tissues, and to
scavenge the latter so as to prevent its polymerization during cell-injury.
DBP also binds fatty acids, and enhances complement activation on neutrophil
chemotaxis by binding to C5a des Arg. Additionally, DBP is known to be
converted in vivo to a potent macrophage and osteoclast activating factor
(DBP-MAF).
The objectives of this proposal are to study various structure-functional
aspects of DBP and DBP-MAF using a multiple-methods approach including
chemical modification of the vitamin D sterol and fatty acid-binding domains
of DBP by affinity/photoaffinity labeling, manipulations of the DBP-gene to
express mutants and segments of DBP and their functional characterization,
determination of the 3-D structures of DBP and DBP-actin complex by X-ray
crystallography, and macrophage-superoxide production and bone resorption
assays (for DBP-MAF activities).
Multi-tasking nature of DBP is directly related to specific
recognition/binding of various ligands by DBP. Such processes are strongly
influenced by the structure of the protein, particularly the 3-D structures
of the domains of the protein that are responsible for such recognition and
binding. Hence, these studies will provide information about the importance
of independent domains in the multi-domained structure of DBP, possible
sharing of a common binding pocket by various endogenous ligands, degree of
cross-talk among various domains, interdependence among various ligands, and
influence of ligand-binding on DBP-MAF activities.
The role of DBP is crucial in the metabolic activation of 1,25(OH)2D3, the
calciotropic hormone, and its tissue-specific delivery, so that the latter
can be responsible in calcium and phosphorus homeostasis, regulation of
growth and maturity of cells, antiproliferation of malignant cells, and
immunoregulation. Interaction of DBP with G-actin is important in the
prevention of actin-polymerization, and clogging of arteries during cellular
injury. On the other hand, macrophage-activation by DBP-MAF has stressed
the possible immunoregulatory property of DBP. Furthermore,
osteoclast-activation (by DBP-MAF) has raised the possibility that this
cytokine may be involved in inflammatory joint diseases such as
osteoarthritis, rheumatoid arthritis, periodontal diseases, etc. The
proposed structure-function studies should be valuable in evaluating
multiple functions and their possible physiological implications of DBP and
DBP-MAF.
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Metabolism of 3H-1 alpha,25-dihydroxyvitamin D3 in cultured human keratinocytes.
培养的人角质形成细胞中 3H-1 α,25-二羟基维生素 D3 的代谢。
DOI:
10.1002/jcb.240590113
发表时间:
1995
期刊:
Journal of cellular biochemistry.
影响因子:
--
作者:
[Ray,S, Ray,R, Holick,MF]
通讯作者:
Holick,MF
Aminopropylation of vitamin D hormone (1 alpha,25-dihydroxyvitamin D3), its biological precursors, and other steroidal alcohols: an anchoring moiety for affinity studies of sterols.
维生素 D 激素(1α,25-二羟基维生素 D3)、其生物前体和其他甾醇的氨丙基化:用于甾醇亲和力研究的锚定部分。
DOI:
10.1016/0039-128x(95)00073-y
发表时间:
1995
期刊:
Steroids
影响因子:
2.7
作者:
[Roy,A, Ray,R]
通讯作者:
Ray,R
Vitamin D receptor interacts with DnaK/heat shock protein 70: identification of DnaK interaction site on vitamin D receptor.
维生素 D 受体与 DnaK/热休克蛋白 70 相互作用:维生素 D 受体上 DnaK 相互作用位点的鉴定。
DOI:
10.1006/abbi.1998.1079
发表时间:
1999
期刊:
Archives of biochemistry and biophysics.
影响因子:
--
作者:
[Swamy,N, Mohr,SC, Xu,W, Ray,R]
通讯作者:
Ray,R
Bacterial expression of human vitamin D-binding protein (Gc2) in functional form.
人类维生素 D 结合蛋白 (Gc2) 的功能形式的细菌表达。
DOI:
10.1006/prep.1996.0720
发表时间:
1997
期刊:
Protein expression and purification.
影响因子:
--
作者:
[Swamy,N, Ghosh,S, Ray,R]
通讯作者:
Ray,R
25-Hydroxy[26,27-methyl-3H]vitamin D3-3 beta-(1,2-epoxypropyl)ether: an affinity labeling reagent for human vitamin D-binding protein.
25-羟基[26,27-甲基-3H]维生素 D3-3 β-(1,2-环氧丙基)醚:人维生素 D 结合蛋白的亲和标记试剂。
DOI:
10.1006/abbi.1995.1323
发表时间:
1995
期刊:
Archives of biochemistry and biophysics.
影响因子:
--
作者:
[Swamy,N, Ray,R]
通讯作者:
Ray,R
共 13 条
Novel vitamin D analog for kidney cancer
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批准号:7471169
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项目类别:
-
资助金额:$18.28万
-
财政年份:2008
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负责人:RAHUL RAY
-
依托单位:
Novel vitamin D analog for kidney cancer
-
批准号:7647277
-
项目类别:
-
资助金额:$21.94万
-
财政年份:2008
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负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:6033064
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项目类别:
-
资助金额:$2.04万
-
财政年份:1999
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负责人:RAHUL RAY
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依托单位:
NON-RADIOACTIVE METHOD FOR 25-OH-D & 1,25 (OH)2D IN BLO
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批准号:2536578
-
项目类别:
-
资助金额:$8.99万
-
财政年份:1997
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负责人:RAHUL RAY
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依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:2328525
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项目类别:
-
资助金额:$3.99万
-
财政年份:1996
-
负责人:RAHUL RAY
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依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
-
批准号:2147002
-
项目类别:
-
资助金额:$0.59万
-
财政年份:1996
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负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:2147003
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项目类别:
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资助金额:$19.55万
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财政年份:1994
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负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:2147000
-
项目类别:
-
资助金额:$0.8万
-
财政年份:1994
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负责人:RAHUL RAY
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依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:2624498
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项目类别:
-
资助金额:$4.36万
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财政年份:1994
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负责人:RAHUL RAY
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依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:2146999
-
项目类别:
-
资助金额:$3.2万
-
财政年份:1994
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负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
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批准号:2855303
-
项目类别:
-
资助金额:$1.64万
-
财政年份:1994
-
负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
-
批准号:2146998
-
项目类别:
-
资助金额:$21.9万
-
财政年份:1994
-
负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
-
批准号:2147001
-
项目类别:
-
资助金额:$18.8万
-
财政年份:1994
-
负责人:RAHUL RAY
-
依托单位:
MOLECULAR PROBING OF VITAMIN D RECEPTOR
-
批准号:2458827
-
项目类别:
-
资助金额:$20.33万
-
财政年份:1994
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负责人:RAHUL RAY
-
依托单位:
BINDING SITE IN VITAMIN D-BINDING PROTEIN
-
批准号:2143725
-
项目类别:
-
资助金额:$14.03万
-
财政年份:1993
-
负责人:RAHUL RAY
-
依托单位:
STRUCTURE/FUNCTION STUDIES OF VITAMIN D BINDING PROTEIN
-
批准号:2905461
-
项目类别:
-
资助金额:$16.04万
-
财政年份:1993
-
负责人:RAHUL RAY
-
依托单位:
STRUCTURE/FUNCTION STUDIES OF VITAMIN D BINDING PROTEIN
-
批准号:2701102
-
项目类别:
-
资助金额:$16.35万
-
财政年份:1993
-
负责人:RAHUL RAY
-
依托单位:
STRUCTURE/FUNCTION STUDIES OF VITAMIN D BINDING PROTEIN
-
批准号:2604997
-
项目类别:
-
资助金额:$0.69万
-
财政年份:1993
-
负责人:RAHUL RAY
-
依托单位:
PROBING THE BINDING SITE IN VITAMIN D BINDING PROTEIN
-
批准号:3245892
-
项目类别:
-
资助金额:$13.37万
-
财政年份:1993
-
负责人:RAHUL RAY
-
依托单位:
BINDING SITE IN VITAMIN D-BINDING PROTEIN
-
批准号:2143727
-
项目类别:
-
资助金额:$14.84万
-
财政年份:1993
-
负责人:RAHUL RAY
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依托单位:
海外基金