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Binding Determinants of Glycoprotein Hormone Receptors

糖蛋白激素受体的结合决定因素

基本信息

批准号：
7332216
负责人：
J DAVID PUETT
金额：
$ 33.92万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7332216
关键词：
Amino Acids Binding Binding Sites Biochemical C-terminal CCR Cells Characteristics Circular Dichroism Complex Crystallization Cyclic AMP Cysteine Data Development Drug Design Epitopes Etiology Female infertility Fertility Figs - dietary Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Fracture G-Protein-Coupled Receptors Glycoproteins Hormone Receptor Hormones Human Hyperthyroidism Investigation Knowledge LIM Domain Leucine-Rich Repeat Ligand Binding Ligands Luteinizing Hormone Manuscripts Measurement Metabolism Methodology Modeling Molds Molecular Molecular Conformation Mutagenesis Mutation N-terminal Numbers Outcome Physiological Precocious Puberty Predisposition Preparation Process Pseudohermaphroditism Receptor Activation Reporter Research Personnel Scanning Signal Transduction Site Site-Directed Mutagenesis Structure Testing Thyrotropin Transmembrane Domain Treatment Protocols Variant base cancer risk extracellular gain of function malignant breast neoplasm molecular modeling mutant programs protein expression protein purification receptor receptor function research study response stoichiometry three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): The glycoprotein hormones (GpHs), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH), regulate fertility and metabolism. Their receptors (GpHRs) are distinguished from most G protein-coupled receptors by the presence of large N-terminal extracellular hormone-binding domains (ECDs). Each ECD consists of nine leucine-rich repeats (LRRs), flanked by N-terminal and C-terminal cysteine-rich regions (NCR and CCR, respectively). The signal of specific hormone binding to the ECD is conveyed by its CCR to the heptahelical transmembrane region (TM). Mutations, activating or inactivating GpHR function, have been identified in hyperthyroidism, precocious puberty and pseudohermaphroditism; moreover, polymorphic variants of LH and FSH receptors have been shown to change the susceptibility to female infertility, breast cancer and risk of bone fractures. AIMS: 1. Identify common hormone-contact sites and key hormone-selective determinants in LRRs of GpHRs, 2. Identify residues in the cysteine-rich regions of GpHRs important for GpH binding and for conveying the binding signal to the TM, and 3. Determine the three-dimensional structure of GpH-GpHR complexes. METHODS: Domain exchange/site-directed mutagenesis, expression, hormone binding and cAMP-dependent reporter activity as readouts, molecular modeling, ECD protein expression, protein purification, crystallization, crystal structure determination. OUTCOME: The results of the proposed studies will increase our knowledge of the molecular mechanisms by which GpHRs recognize the 'correct' GpH, as well as the step-wise propagation of the signal to the TM following ligand binding. These data, in combination with the mutant 'gain-of-function' GpHRs, will be molded into a general model of GpHR activation, essential for the development of better treatment protocols and the rational design of drugs that change receptor activity. Moreover, these data may yield a better understanding of the etiology of different pathological states known for some GpH-GpHR pairs.

说明(申请人提供)：糖蛋白激素(GPHS)、黄体生成素(LH)、卵泡刺激素(FSH)和促甲状腺激素(TSH)，调节生育和新陈代谢。它们的受体(GpHR)不同于大多数G蛋白偶联受体，因为存在大的N末端细胞外激素结合结构域(ECDs)。每个ECD由9个富含亮氨酸的重复序列(LRR)组成，两侧分别有N端和C端的半胱氨酸富集区(NCR和CCR)。特定激素与ECD结合的信号由其CCR传递到七螺旋跨膜区(TM)。在甲状腺功能亢进症、性早熟和假两性畸形中，已经发现了激活或失活GPHR功能的突变；此外，已证明黄体生成素受体和卵泡刺激素受体的多态变异改变了女性不孕不育、乳腺癌和骨折的易感性。目的：1.确定GpHR的LRR中常见的激素接触位点和关键激素选择决定因素；2.确定GpHR半胱氨酸富集区中对GPH结合和向TM传递结合信号重要的残基；3.确定GPH-GPHR复合体的三维结构。方法：结构域交换/定点突变、表达、激素结合和cAMP依赖的报告活性为读数、分子模拟、ECD蛋白表达、蛋白纯化、结晶、晶体结构测定。结果：拟议的研究结果将增加我们对GpHR识别“正确的”GPH的分子机制的了解，以及在配体结合后信号逐步传播到TM的知识。这些数据与突变的“功能增益”GpHR结合在一起，将被塑造成GPHR激活的一般模型，这对于开发更好的治疗方案和合理设计改变受体活性的药物至关重要。此外，这些数据可能会更好地理解一些GPH-GPHR对已知的不同病理状态的病因。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of follicle-stimulating hormone-selective beta-strands in the N-terminal hormone-binding exodomain of human gonadotropin receptors.

人促性腺激素受体 N 末端激素结合外域中促卵泡激素选择性 β 链的鉴定。

DOI：
10.1210/me.2005-0202
发表时间：
2006
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
0
作者：
Vischer,HenryF;Granneman,JokeCM;Bogerd,Jan
通讯作者：
Bogerd,Jan

Mutations in a novel, cryptic exon of the luteinizing hormone/chorionic gonadotropin receptor gene cause male pseudohermaphroditism.

DOI：
10.1371/journal.pmed.0050088
发表时间：
2008-04-22
期刊：
PLoS medicine
影响因子：
15.8
作者：
Kossack N;Simoni M;Richter-Unruh A;Themmen AP;Gromoll J
通讯作者：
Gromoll J

Determining the affinity of hormone-receptor interaction.

确定激素-受体相互作用的亲和力。

DOI：
10.1007/978-1-60327-378-7_1
发表时间：
2009
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Puett,David;Angelova,Krassimira
通讯作者：
Angelova,Krassimira

The luteinizing hormone receptor: insights into structure-function relationships and hormone-receptor-mediated changes in gene expression in ovarian cancer cells.

DOI：
10.1016/j.mce.2010.04.025
发表时间：
2010-11-25
期刊：
MOLECULAR AND CELLULAR ENDOCRINOLOGY
影响因子：
4.1
作者：
Puett, David;Angelova, Krassimira;da Costa, Marcelo Rocha;Warrenfeltz, Susanne W.;Fanelli, Francesca
通讯作者：
Fanelli, Francesca

Identification of a luteinizing hormone-selective determinant in the exodomain of a follicle-stimulating hormone receptor.

卵泡刺激素受体外域中黄体生成素选择性决定簇的鉴定。