STRUCTURE OF UROKINASE RECEPTOR IN COMPLEX TO ITS INHIBITORS

尿激酶受体与其抑制剂复合物的结构

• 批准号: 8363341
• 负责人: Mingdong Huang
• 金额: $ 0.61万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363341
• 关键词: Basic Science; Cancer Etiology; Cessation of life; Complex; Crystallography; Down-Regulation; Funding; Genes; Grant; Human; Lead; Ligand Binding; Ligands; Light; Malignant Neoplasms; Molecular; Mus; National Center for Research Resources; Neoplasm Metastasis; Plasminogen; Principal Investigator; Research; Research Infrastructure; Resources; Series; Source; Staging; Structure; Surface; Synchrotrons; Techniques; Therapeutic; Tumor Cell Invasion; United States National Institutes of Health; Urokinase Plasminogen Activator Receptor; cell motility; cost; drug development; inhibitor/antagonist; pre-clinical; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Complications resulted from tumor metastasis are the major causes of cancer death. Urokinase receptor (uPAR) is widely accepted as a target for treatment of tumor metastasis. Suppression of uPAR expression has shown to reverse tumor invasion and inhibit tumor metastasis on several cancers to various extents. Urokinase receptor is critical for pericellular plasminogen activation and is over-expressed in the tumor-associated stroma and in some tumors. Down-regulation of uPAR expression by several approaches, e.g. anti-gene techniques, has shown to reverse tumor invasion and inhibit tumor metastasis on several cancers to various extents. Despite that many types of uPAR antagonists being identified through over a decade of studies, none of them was moved to preclinical stage. We have identified the major challenges for the drug development of uPAR inhibitors through a series of structural studies.We determined a series of crystal structures of human and murine uPAR-ligand complexes. These structures reveals a deep ligand binding pocket (14 ¿) on uPAR surface, suggesting the possibility to intervene with this interaction using small molecular inhibitors. Our studies also show that human and murine uPAR share a common region for ligand recognition, and thus possibility to develop inhibitors for both human and murine uPAR.We have developed strategies to identify small molecular inhibitors of uPAR. Structural studies of uPAR-inhibitor complexes are an integral part of our stragegies. The inhibitors identified from this study will not be useful for basic research on their effects on cell migration mechanism, but may also lead to the discovery of therapeutics for the treatment of tumor metastasis.

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