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Identifying Key Structural Interactions in Heparan Sulfate-Protein Complexes

鉴定硫酸乙酰肝素-蛋白质复合物中的关键结构相互作用

基本信息

批准号：
10715985
负责人：
Kari Joanne Pederson
金额：
$ 16.27万
依托单位：
CALIFORNIA STATE UNIV-DOMINGUEZ HILLS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715985
关键词：
Autoimmune Diseases Binding Binding Proteins Biological Biological Process Blood Circulation Blood Coagulation Factor CCL2 gene CXCL10 gene California Calorimetry Carbohydrates Catalysis Categories Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Culture Techniques Cell surface Cells Characteristics Coagulation Process Collaborations Complex Core Protein Data Disaccharides Disease Progression Docking Drug Targeting Early identification Extracellular Matrix Foundations Funding Future Glycosaminoglycans Goals Growth Factor HIV-1 Heparitin Sulfate Hispanic-serving Institution Human IL8 gene Immune response Infection Infection prevention Inflammation Isotope Labeling Libraries Life Cycle Stages Ligands Mammalian Cell Membrane Proteins Methodology Modeling Molecular Molecular Conformation Nuclear Magnetic Resonance Process Proteins Proteoglycan RANTES Research Role Signal Transduction Spectrum Analysis Stromal Cell-Derived Factor 1 Structural Models Structural Protein Structure Surface Plasmon Resonance Testing Titrations Training Universities Virus Virus Diseases cell growth regulation chemokine cytokine drug development experimental analysis extracellular institutional capacity nuclear transfer programs protein complex receptor screening sugar tissue repair undergraduate student viral entry inhibitor virtual

项目摘要

Project Summary Glycosaminoglycans (GAGs), such as heparan sulfate (HS), are important components of the extracellular matrix of all cells. The extraordinary structural diversity of GAGs enables them to interact with a wide variety of biological molecules, but primarily proteins, to modulate biological processes, such as cell adhesion, tissue repair, coagulation, and immune response, among many others. Additionally, a number of different viruses, including HIV-1, initiate infection of cells by binding to cell surface GAGs. Unfortunately, the diversity of potential binding motifs in GAG sequences has made identification of relevant sequences challenging. In particular, heparan sulfate (HS) is the most structurally diverse, with sixteen unique disaccharide configurations and 256 unique tetrasaccharide configurations. Significant progress has been made in recent years developing libraries of synthetic HS oligomers, allowing for detailed experimental structural studies of HS-protein complexes. Understanding the structural basis of these interactions is key to drug development and the HS binding protein-HS (HSBP-HS) interaction studies to date have been either non-structural or computational. The overall goal of this project is to utilize these recently developed synthetic HS libraries and NMR-based structural models to identify key interactions. HIV-1 p17 will be used for initial studies because it is very important in many stages of the life cycle of HIV-1. Heparan sulfate receptors are known to influence growth factor signaling, cell adhesion, and enzymatic catalysis on human cells. Thus, this interaction may be one of the deciding factors for disease progression in humans infected with HIV-1. In Aim 1, a library of synthetic HS tetrasaccharides will be screened for binding to human immunodeficiency virus type 1 (HIV-1) p17 protein to identify the sequence-specific HS characteristics of the preferred binding oligomers. In Aim 2, the HSBP-HS complexes of both strong and weak binding sequences will be studied via nuclear magnetic resonance (NMR) to model the structure of the complex and identify key interactions for future drug development. After the methodology is established, HS-binding chemokines will be screened in Aim 3 to identify suitable targets for future NMR studies.

项目总结