Drug Design: Glutamate Receptor Signaling
Drug Design: Glutamate Receptor Signaling
批准号:
6623499
负责人:
DALE F MIERKE
金额:
$14.78万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-04-01 至 2005-03-31
关键词:
AMPA receptors NMDA receptors X ray crystallography alcoholism /alcohol abuse biological signal transduction computer simulation drug addiction drug design /synthesis /production glutamate receptor green fluorescent proteins immunoprecipitation intermolecular interaction molecular dynamics nuclear magnetic resonance spectroscopy physical model protein binding protein signal sequence protein structure function synapses transcription factor
中文摘要
描述(由申请人提供):
最近的研究提供了强有力的证据表明,谷氨酸受体信号,通过
AMPA/红藻氨酸和NMDA受体在药物寻找中发挥机制作用
成瘾是一种谷氨酸依赖性生理反应。
AMPA/红藻氨酸和NMDA受体拮抗剂具有临床应用潜力
与酒精和其他药物成瘾有关的综合征。虽然
已经证明,AMPA、红藻氨酸和NMDA受体存在多种亚型,
由于高度同源性,难以开发亚型特异性拮抗剂
而不是它们的配体结合口袋。相比之下,谷氨酸受体亚型可以
与不同的细胞内信号级联通过突触相关
蛋白质(SAP)。SAP(例如,SAP 90和SAP 97)由五个独立的
结构域:三个PDZ结构域(PDZ 1、PDZ 2、PDZ 3),src-同源3结构域(SH 3),
和鸟苷酰激酶样结构域(GK)。我们的研究表明,PDZ结构域
决定受体亚型的选择,而分子内相互作用
SAP不同结构域之间的相互作用调节受体功能。这里我们
我建议开发肽和肽模拟物,
特异性谷氨酸受体与SAP 90和SAP 97的相互作用,
下游信号蛋白。我们的目标是从结构上表征
SAP 90和SAP 97之间的相互作用。为了实现这一点,
高分辨率核磁共振和计算机模拟将被用来确定
PDZ 1和SH 3的结构特征,而与其他结构域的复合物,
SAP 90和SAP 97以及来自NMDA、AMPA和红藻氨酸的片段
受体。高分辨率的结构将提供深入了解
受体、SAP和调节蛋白之间的相互作用,
负责受体的信号传导、聚集和再循环。
将实验确定的结构特征详细描述为
SAP 90和SAP 97的分子模型将允许合理设计
这些相互作用的分子抑制剂。这样的分子将允许
更好地理解SAP 90和SAP 97的功能,并提供
治疗药物成瘾的新途径。
英文摘要
DESCRIPTION (provided by applicant):
Recent studies provide strong evidence that glutamate receptor signaling, via
both AMPA/kainate and NMDA receptors, play a mechanistic role in drug seeking
responses and that addiction is a form of glutamate-dependent phisticity.
AMPA/kainate and NMDA receptor antagonists have potential for clinical
syndromes associated with addiction to alcohol and other drugs. Although
numerous subtypes of AMPA, kainate, and NMDA receptors exist, it has proven
difficult to develop subtype specific antagonists because of the high homology
ot their ligand binding pockets. In contrast, glutamate receptor subtypes can
couple to different intracellular signaling cascades via synaptic associated
proteins (SAPs). SAPs (e.g., SAP9O and SAP97) are made up of five separate
domains: three PDZ domains (PDZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3),
and a guanyl kinase-like domain (GK). Our studies show that the PDZ domains
determine the selection of receptor subtype, while intra-molecular interactions
between the different domains of SAPs regulate receptor function. Here we
propose to develop peptides and peptidomimetics that will disrupt the molecular
interactions of specific glutamate receptors with SAP90 and SAP97 and
downstream signaling proteins. We aim to structurally characterize the
inter-domain interactions of SAP90 and SAP97. To accomplish this,
high-resolution NMR and computer simulations will be utilized to determine the
structural features of PDZ1 and SH3 while complexed with the other domains of
SAP90 and SAP97 as well as fragments from the NMDA, AMPA, and kainate
receptors. The high-resolution structures will provide insight into the
interactions between the receptors, SAPs, and regulatory proteins, which are
responsible for the signaling, clustering and recycling of the receptors.
Incorporating the experimentally determined structural features into detailed
molecular models of SAP90 and SAP97 will allow for the rational design of
molecular inhibitors of these interactions. Such molecules will allow for a
greater understanding of the function of SAP90 and SAP97 as well as provide a
novel route for the treatment of drug addiction.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Molecular Tools Core
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批准号:10647702
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项目类别:
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资助金额:$31.8万
-
财政年份:2016
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负责人:DALE F MIERKE
-
依托单位:
Molecular Tools Core
-
批准号:10271747
-
项目类别:
-
资助金额:$31.8万
-
财政年份:2016
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负责人:DALE F MIERKE
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依托单位:
Molecular Tools Core
-
批准号:10460272
-
项目类别:
-
资助金额:$31.8万
-
财政年份:2016
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负责人:DALE F MIERKE
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依托单位:
Acquisition of 700 MHz NMR for Automated Chemical/Peptide Library Screening
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批准号:7834726
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项目类别:
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资助金额:$183.33万
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财政年份:2010
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负责人:DALE F MIERKE
-
依托单位:
Acquisition of a CD Spectrophotometer
-
批准号:7046996
-
项目类别:
-
资助金额:$10.47万
-
财政年份:2006
-
负责人:DALE F MIERKE
-
依托单位:
Drug Design: Glutamate Receptor Signaling
-
批准号:6928977
-
项目类别:
-
资助金额:$34.88万
-
财政年份:2004
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负责人:DALE F MIERKE
-
依托单位:
Drug Design: Glutamate Receptor Signaling
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批准号:7477806
-
项目类别:
-
资助金额:$33.43万
-
财政年份:2004
-
负责人:DALE F MIERKE
-
依托单位:
Drug Design: Glutamate Receptor Signaling
-
批准号:7101814
-
项目类别:
-
资助金额:$34.06万
-
财政年份:2004
-
负责人:DALE F MIERKE
-
依托单位:
Drug Design: Glutamate Receptor Signaling
-
批准号:7556423
-
项目类别:
-
资助金额:$33.07万
-
财政年份:2004
-
负责人:DALE F MIERKE
-
依托单位:
Drug Design: Glutamate Receptor Signaling
-
批准号:6830660
-
项目类别:
-
资助金额:$34.88万
-
财政年份:2004
-
负责人:DALE F MIERKE
-
依托单位:
Drug Design: Glutamate Receptor Signaling
-
批准号:6466373
-
项目类别:
-
资助金额:$14.83万
-
财政年份:2002
-
负责人:DALE F MIERKE
-
依托单位:
CONFORMATIONAL CONSEQUENCES OF A MEMBRANE ENVIRONMENT
-
批准号:6188482
-
项目类别:
-
资助金额:$5.13万
-
财政年份:1999
-
负责人:DALE F MIERKE
-
依托单位:
CONFORMATIONAL CONSEQUENCES OF A MEMBRANE ENVIRONMENT
-
批准号:2695497
-
项目类别:
-
资助金额:$5.13万
-
财政年份:1999
-
负责人:DALE F MIERKE
-
依托单位:
CONFORMATIONAL CONSEQUENCES OF A MEMBRANE ENVIRONMENT
-
批准号:6394929
-
项目类别:
-
资助金额:$3.72万
-
财政年份:1999
-
负责人:DALE F MIERKE
-
依托单位:
CHOLECYSTOKININ A RECEPTOR
-
批准号:6279675
-
项目类别:
-
资助金额:$0.95万
-
财政年份:1998
-
负责人:DALE F MIERKE
-
依托单位:
PARATHYROID HORMONE
-
批准号:6279674
-
项目类别:
-
资助金额:$7.07万
-
财政年份:1998
-
负责人:DALE F MIERKE
-
依托单位:
G PROTEIN/RECEPTOR ASSOC--STRUCTURAL CHARACTERIZATION
-
批准号:2193479
-
项目类别:
-
资助金额:$10.51万
-
财政年份:1996
-
负责人:DALE F MIERKE
-
依托单位:
G PROTEIN/RECEPTOR ASSOC--STRUCTURAL CHARACTERIZATION
-
批准号:2718532
-
项目类别:
-
资助金额:$11.2万
-
财政年份:1996
-
负责人:DALE F MIERKE
-
依托单位:
G PROTEIN/RECEPTOR ASSOC--STRUCTURAL CHARACTERIZATION
-
批准号:2910232
-
项目类别:
-
资助金额:$11.2万
-
财政年份:1996
-
负责人:DALE F MIERKE
-
依托单位:
G Protein Receptor--Structural Characterization
-
批准号:6603220
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项目类别:
-
资助金额:$26.67万
-
财政年份:1996
-
负责人:DALE F MIERKE
-
依托单位:
海外基金