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Structural Biology of Multi-Domain Nuclear Receptor Complexes

多域核受体复合物的结构生物学

基本信息

批准号：
9159659
负责人：
FRAYDOON RASTINEJAD
金额：
$ 38.27万
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：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9159659
关键词：
Architecture Binding Biochemical Biological Assay Cells Communication Complex Coupling Crystallization DNA DNA Binding DNA Binding Domain Developmental Process Dietary Fats Direct Repeats Drug Prescriptions Elements Embryonic Development Family Fatty Acids Fertility Gene Expression Genetic Transcription Heme Human Individual Lead Learning Length Ligand Binding Ligand Binding Domain Ligands Link Mediating Metabolism Molecular N-terminal Nuclear Receptors PPAR gamma Pathway interactions Peptides Physiological Progesterone Receptors Property RXR Reporting Reproductive Process Response Elements Retinoic Acid Receptor Retinoic Acid Response Element Retinoids Series Signal Transduction Site Steroid Receptors Steroids Structure Surface X ray diffraction analysis X-Ray Diffraction base lipid metabolism lipophilicity monomer polypeptide progesterone receptor A programs protein complex receptor receptor binding receptor function response small molecule steroid hormone structural biology transcription factor

项目摘要

PROJECT SUMMARY Lipophilic molecules including steroid hormones, retinoids, fatty acids, and dietary lipids control reproductive, developmental and metabolic processes by directly binding and modulating the activities of nuclear receptors (NRs). NRs bind to DNA and regulate the expression of gene programs that lead to physiological responses to their small-molecule ligands. Structural studies over the past few decades have focused primarily on just the ligand binding domains (LBDs) or DNA-binding domains (DBDs) of NRs, but were unable to reveal how the multi-domain architectures are integrated in a quaternary structure. To understand the physical and functional coupling of different receptor domains, we have been conducting X-ray diffraction studies involving full-length and multi-domain nuclear receptor complexes in their functionally revealing complexes bound to DNA, ligands, and coregulator peptides. Our previous studies revealed that DBDs and LBDs of the PPARγ-RXRα heterodimer and HNF-4α homodimer are physically linked through a highly interfaced arrangement of domain surfaces, some of which are DNA-dependent. We now propose to considerably broaden our understanding of the domain-domain connections and allosteric communications in the nuclear receptor family. We will obtain the crystal structures of three new NR complexes that include the Retinoic-Acid Receptor (RAR) heterodimer with Retinoid X Receptor (RXR), the progesterone receptor (PR) homodimer, and the monomeric Rev-Erbβ receptor. These differing NRs also discern distinct response elements consisting of direct repeats, inverted repeats, and single half-sites, thus, distinctive domain-domain interfaces are anticipated as compared to previously seen in PPARγ-RXRα or HNF-4α. We further propose to conduct a series of complementary biochemical and cell-based functional studies to probe and quantitate the mechanistic underpinning of inter- domain allosteric signal propagation in these receptor complexes.

项目总结