HIGH RESOLUTION STRUCTURAL STUDIES OF LIGAND BINDING DOMAIN OF LDL RECEPTOR

LDL受体配体结合域的高分辨率结构研究

• 批准号: 6355151
• 负责人: Stephen C. Blacklow
• 金额: $ 0.21万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355151
• 关键词: biological products; biomedical resource; drug /agent; nucleic acids

The low-density lipoprotein receptor (LDLR) is the primary mechanism for the uptake of plasma cholesterol into cells and serves as a prototype for a growing family of cell surface receptors. These receptors all utilize tandemly-repeated LDL-A modules to bind their ligands. Each LDL-A module is about 40 residues long, has 6 conserved cysteine residues and contains a conserved acidic region near the C-terminus that serves as a calcium binding site. The structure of the interface presented for ligand binding by these modules, and the basis for their specificity and affinity in ligand binding, is not yet known. We have purified recombinant molecules corresponding to LDL-A modules five (LR5), six (LR6*), as well as the module five-six pair (LR5-6*) of the LDL receptor. Calcium is required to establish native disulfide bonds and to maintain the structural integrity of LR5, LR6*, and the LR5-6* module pair. Comparison of proton and multidimensional heteronuclear NMR spectra of individual modules to those of the module pair indicates that most of the significant spectroscopic changes lie within the linker region between modules and that little structural interaction occurs between the cores of modules 5 and 6 in the 5-6 pair. These findings strongly support a model in which each module is essentially structurally independent of the other. Assignments for the backbone and for most of the side chain resonances are complete for LR5, LR6*, and for the LR5-6* module pair. Current efforts are focused on completion of the side chain assignments and calculation of the solution structures of LR6* and LR5-6*. I

低密度脂蛋白受体（LDLR）是主要的