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Identification of Allsoteric Ligands for Hepatic Nuclear Factor 4-alpha

肝核因子 4-α 变构配体的鉴定

基本信息

批准号：
8775220
负责人：
FRAYDOON RASTINEJAD
金额：
$ 55.78万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-05 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775220
关键词：
Affinity Architecture Binding Biochemical Biological Assay Blood Glucose Cataloging Catalogs Cells Complex Consensus DNA DNA Binding DNA Binding Domain Diabetes Mellitus Disease Dose Employee Strikes Family Fatty Acids Gene Targeting Genes Genetic Transcription Glucose Goals Hepatic Human Hypoglycemia Inherited Insulin Knowledge Length Libraries Ligand Binding Domain Ligands Link Liver Mutagenesis Mutate Mutation Neonatal Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Pancreas Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiology Platelet Factor 4 Point Mutation Population Post-Translational Protein Processing Preclinical Drug Evaluation Property Proteins Resolution Response Elements Site Specificity Structure Testing Therapeutic Agents Time Work assay development base functional restoration glucose production high throughput screening human HNF4A protein member mutant patient population polypeptide receptor response scaffold screening small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): The hepatocyte nuclear factor 4-alpha (HNF4) is a member of the nuclear receptor family of transcription factors. HNF4 controls genes in the liver and pancreas related to insulin and glucose production. Mutations in HNF4 cause Maturity Onset of Diabetes in Young 1 (MODY1), and hyperinsulinemic hypoglycemia (HH) in humans. Members of the nuclear receptor superfamily have a hydrophobic pocket inside their ligand binding domains (LBDs). Traditional drug screening strategies exploit these pockets, guided by known structures of isolated LBDs. The field has lacked high-resolution structures for full-length receptors, and therefore not considered the possibility of other druggable sites elsewhere in these proteins. We have obtained a complete crystal structure HNF4 homodimer, in a functionally revealing complex with its DNA response element. This structure unexpectedly reveals two sites at domain-domain junctions, where small molecules could bind. Our mutational studies, and previous knowledge of post-translational modifications, show these sites can allosterically regulate the DNA affinity of HNF4 . We propose a high-throughput screening campaign, together with confirmatory assays and mechanistic studies that exploit these new sites in HNF4 . Our goal is to identify potentiators of DNA binding that benefit certain MODY1 and HH disease populations where receptor-DNA binding is compromised by point mutations in HNF4 .

描述（由申请人提供）：肝细胞核因子4- α (HNF4)是核受体转录因子家族的成员。HNF4控制着肝脏和胰腺中与胰岛素和葡萄糖产生相关的基因。HNF4基因突变导致年轻1型糖尿病（MODY1）和人类高胰岛素性低血糖（HH）的成熟发病。核受体超家族的成员在其配体结合域（lbd）内具有疏水性口袋。传统的药物筛选策略利用这些口袋，以已知的分离lbd结构为指导。该领域缺乏全长受体的高分辨率结构，因此没有考虑到这些蛋白质中其他可药物位点的可能性。我们获得了一个完整的晶体结构的HNF4同型二聚体，在一个功能揭示的复合体与其DNA响应元件。这种结构出人意料地揭示了两个区域连接的位点，在那里小分子可以结合。我们的突变研究和先前对翻译后修饰的了解表明，这些位点可以变构调节HNF4的DNA亲和力。我们建议开展高通量筛选活动，以及利用HNF4中这些新位点的验证性分析和机制研究。我们的目标是鉴定DNA结合的增强剂，使某些MODY1和HH疾病人群受益，这些人群的受体-DNA结合受到HNF4点突变的损害。