Protein Structure

蛋白质结构

• 批准号: 7965279
• 负责人: alexander wlodawer
• 金额: $ 177.47万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965279
• 关键词: ATP-Dependent Proteases; Acquired Immunodeficiency Syndrome; Antibodies; Antiviral Agents; Area; Aspartic Endopeptidases; Binding; Carbohydrates; Complex; Crystallography; Cytokine Receptors; Data; Databases; Deposition; Development; Disaccharides; Drug resistance; Enzymes; Family; Feline Immunodeficiency Virus; HIV Infections; HIV Protease; Human T-lymphotropic virus 1; Interferons; Interleukin-10; Investigation; Laboratories; Lectin; Malignant Neoplasms; Mannose; Methodology; Monosaccharides; Oligosaccharides; Organism; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Property; Protease Domain; Proteins; Research; Resolution; Serine; Source; Structure; Structure-Activity Relationship; Techniques; Variant; Work; X ray diffraction analysis; X-Ray Diffraction; allergen Bla g 2; base; cockroach allergen; cytokine; drug development; inhibitor/antagonist; interest; interleukin 20; interleukin-19; interleukin-22; leukemia; method development; preclinical study; prevent; programs; protein complex; protein structure; protein structure function; receptor

In the past several years, our work has concentrated in four distinct areas. Crystallographic studies of proteases Crystallographic studies of proteases have been an important area of research of this Section since its establishment. We have been particularly active in the investigation of structure-function relationship in aspartic proteases, including clinically important retroviral enzymes. Our studies of HIV protease, although no longer a major target of active research, are still ongoing and concentrate on the investigation of drug-resistant variants and their complexes with inhibitors. We have investigated retroviral proteases from several other sources such as FIV, RSV, and HTLV-1. A number of inhibitor complexes of the latter enzyme have been analyzed, with the aim of assisting in the development of drugs against HTLV-caused leukemia. Cockroach allergen Bla g 2 was shown to be an inactive aspartic protease and we solved the structures of two complexes with different specific antibodies. We have established an extensive program of investigating serine-carboxyl peptidases (sedolisins), a family that was first characterized based on crystal structures solved in this laboratory and that is found in many different organisms. We are also investigating a bacterial ATP-dependent protease Lon, finding that is proteolytic domain has a unique fold and thus establishes a new family of proteases with a Ser-Lys catalytic dyad. Lectins with antiviral activity We have been involved in studies of several lectins with antiviral activities, some of them currently being in pre-clinical trials as potential drugs preventing HIV infection. We have solved the structure of griffithsin, as free protein and complexed with a number of mono- and disaccharides, explaining the structural basis for its tight binding to branched mannose-rich carbohydrates. We have reengineered griffithsin into a monomeric form and solved its structure with a complex oligosaccharide, elucidating the basis of its antiviral properties. We have also solved atomic-resolution structure of another lectin, scytovirin. Cytokines and cytokine receptors Our Section has been investigating the crystal structures of several cytokines and has made progress in preparing their receptor complexes. We have purified and crystallized complexes of IL-10 with its specific receptor and are studying complexes of several other cytokines related to IL-10, such as IL-19, IL-20, and IL-22. We have solved the structure of lambda interferon complexed with its receptor. Development of crystallographic methodology We have been investigating the problems related to phasing of diffraction data, deposition of structures in the Protein Data Bank, and improvement of the quality of deposited crystallographic data.

在过去几年中，我们的工作集中在四个不同的领域。 蛋白酶的晶体学研究 这是该部门自成立以来的重要研究领域。我们尤其 在天冬氨酸蛋白酶的结构-功能关系的研究中是活跃的， 包括临床上重要的逆转录病毒酶。我们对HIV蛋白酶的研究，虽然没有 长期以来一直是积极研究的主要目标，目前仍在进行中，并专注于 研究耐药变异体及其与抑制剂的复合物。我们有 研究了来自几种其他来源的逆转录病毒蛋白酶，如FIV、RSV和HTLV-1。一 已经分析了后一种酶的抑制剂复合物的数量，目的是 协助开发抗HTLV引起的白血病的药物。蟑螂变应原Bla g 2 是一种无活性的天冬氨酸蛋白酶，并解出了两种复合物的结构 用不同的抗体我们已经建立了一个广泛的调查计划 丝氨酸羧基肽酶（sedolisins），一个家族，首先基于 晶体结构在这个实验室里得到了解决，在许多不同的生物体中都有发现。我们 他们还研究了一种细菌ATP依赖性蛋白酶Lon， 结构域具有独特的折叠，因此建立了一个新的蛋白酶家族， 催化二元体具有抗病毒活性的凝集素 具有抗病毒活性的凝集素，其中一些目前正在进行临床前试验， 预防艾滋病毒感染的潜在药物。我们已经解决了griffithsin的结构， 蛋白质，并与一些单糖和二糖复合，解释了结构 其与富含甘露糖的支链碳水化合物紧密结合的基础。我们重新设计了 将griffithsin转化为单体形式并用复合寡糖解析其结构， 阐明其抗病毒特性的基础。我们还解决了原子分辨率 另一种凝集素scytovirin的结构。细胞因子和细胞因子受体 研究了几种细胞因子的晶体结构， 它们的受体复合物。我们已经纯化并结晶了IL-10与其 目前正在研究与IL-10相关的其他几种细胞因子的复合物， 如IL-19、IL-20和IL-22。我们已经解决了λ干扰素与 它的受体。结晶学方法学的发展我们一直在研究 与衍射数据的定相、蛋白质数据中结构的沉积有关的问题 和提高沉积的晶体学数据的质量。