CHEMICAL PROBES FOR STUDYING EUKARYOTIC CELL BIOLOGY

用于研究真核细胞生物学的化学探针

• 批准号: 7724165
• 负责人: Jack Taunton
• 金额: $ 0.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7724165
• 关键词: Affinity; Angiogenic Factor; Base Sequence; Binding; Bioinformatics; Cells; Cellular biology; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Cyclodepsipeptides; Cysteine; Endoplasmic Reticulum; Eukaryotic Cell; Family; Funding; Grant; Human; Inflammatory; Institution; Methods; Positioning Attribute; Protein Kinase Inhibitors; Research; Research Personnel; Resources; Sequence Alignment; Source; Structure; Structure-Activity Relationship; United States National Institutes of Health; Variant; design; inhibitor/antagonist; protein kinase inhibitor; secretory protein

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have developed a structural bioinformatics method for designing highly selective inhibitors of protein kinases. We use a structure-based sequence alignment of the human kinome to identify non-conserved cysteines near or within the ATP binding pocket. We then identify reversible inhibitors that bind with modest affinity and selectivity. We design and synthesize derivatives with electrophilic substituents at positions predicted to be proximal to the non-conserved cysteine. In another project, we have discovered a family of cyclodepsipeptides, termed 'cotransins', which potently inhibit the expression of several pro-inflammatory and pro-angiogenic factors in primary human cells. These compounds act at the endoplasmic reticulum and block the cotranslational translocation of a subset of human secretory proteins. We are currently synthesizing cyclopeptide variants and determining structure-activity relationships.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构为 中心，但不一定是研究者所在的机构。 我们开发了一种结构生物信息学方法，用于设计高选择性的蛋白激酶抑制剂。 我们使用基于结构的人类激酶组的序列比对来识别ATP结合口袋附近或内部的非保守半胱氨酸。 然后，我们确定可逆的抑制剂，结合适度的亲和力和选择性。 我们设计和合成的衍生物与亲电取代基的位置预测是接近非保守的半胱氨酸。 在另一个项目中，我们发现了一个称为“cotransins”的环缩肽家族，其有效地抑制原代人类细胞中几种促炎因子和促血管生成因子的表达。 这些化合物作用于内质网并阻断人分泌蛋白亚类的共翻译易位。 我们目前正在合成环肽变体并确定结构-活性关系。