Structural Biology Shared Facility

结构生物学共享设施

• 批准号: 10362784
• 负责人: William J. Placzek
• 金额: $ 37.8万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-28 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362784
• 关键词: ABCB1 gene; Advisory Committees; Alabama; American; Binding; Biochemistry; Biophysics; Biotechnology; Calmodulin; Cancer Center; Cancer Center Support Grant; Cancer Research Project; Cellular biology; Chemicals; Clinical; Clinical Trials; Complex; Comprehensive Cancer Center; Computer Models; Computers; Consultations; Crystallization; Crystallography; Cutaneous T-cell lymphoma; Data Collection; Drug Targeting; Equipment; Exhibits; Faculty; Feedback; Funding; Goals; Grant; Group Structure; Human; Image; Immunology; Immunotherapeutic agent; Individual; Inflammation; Investigational Therapies; Journals; Libraries; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Membrane Proteins; Molecular; Molecular Analysis; Multi-Drug Resistance; NCI Center for Cancer Research; Nuclear Magnetic Resonance; Optics; Pharmaceutical Preparations; Pharmacology; Phase Ib Trial; Proteins; Public Facilities; Publishing; RXR; RXRA gene; Recovery; Research; Research Support; Resistance; Resources; Roentgen Rays; Scanning; Science; Services; Site Visit; Structure; Students; Sum; Synchrotrons; System; Techniques; Training and Education; Translational Research; Translations; United States National Institutes of Health; University of Alabama at Birmingham Cancer Center; Work; X-Ray Crystallography; anticancer research; aqueous; base; biophysical properties; cancer cell; cancer chemoprevention; chemical synthesis; chemotherapy; design; detector; drug candidate; drug discovery; fundamental research; imaging system; improved; inhibitor/antagonist; instrument; instrumentation; interest; kinase inhibitor; malignant breast neoplasm; member; metabolomics; nanocrystal; novel; novel therapeutics; outreach; programs; protein structure; recruit; response; screening; src-Family Kinases; structural biology; synergism; trend; virtual screening; web site

MOLECULAR ANALYSIS / TRANSLATION GROUP STRUCTURAL BIOLOGY SHARED FACILITY (SBSF) ABSTRACT The Structural Biology Shared Facility (SBSF) provides CCC members access to critical biophysical facilities including: 1) X-ray crystallographic data collection (via in-house x-ray systems and dedicated access to two synchrotron beam lines via membership in the Southeastern Collaborative Access Team (SERCAT) at the Argonne Synchrotron Facility; 2) high-throughput nano-crystallization services for aqueous and membrane proteins, 3) Nuclear Magnetic Resonance (NMR) instrumentation ranging from 850 MHz to 300 MHz and 4) biophysical measurements including high-throughput differential scanning and isothermal micro-calorimeters. In addition to providing access to the state-of-the-art instrumentation, the SBSF supports the Cancer Center members through service and consultation over a wide array of structural biology projects ranging from: 1) structural determination of proteins, protein-protein and protein-ligand complexes of interest in different cancers; 2) structure-based virtual screening of compound libraries; 3) drug discovery research in general including structure-based chemical syntheses; 4) fragment-based design of new inhibitors; 5) screening of compound libraries by NMR and crystallography; 6) applications of NMR-metabolomics in cancer research, and on membrane proteins as drug targets. The SBSF works closely with the Alabama Drug Discovery Alliance (ADDA) to support the research efforts of the CCC members developing novel drugs to treat multiple forms of cancer. During the past funding period the facility was used to support fundamental and translational research for 105 users, 78 of which are CCC members with NIH funding exceeding $60 million. SBSF usage resulted in more than 50 different novel protein structures published in a variety of journals including Science, PNAS, Biochemistry, JBC, JMB, Cell Biology, Molecular Pharmacology, Trends in Biotechnology, Acta-D, Acta-F and Structure. Examples of value added via the shared facility include: a) determination of more than 20 x-ray structures of the retinoid X receptor, RXR, a protein implicated in breast cancer and cutaneous T-cell lymphoma. A clinical drug candidate is currently in human phase 1b trials at NCI; b) Identification of novel Src kinase inhibitors (initial hits) that target the Src/calmodulin interaction and exhibit anti-pancreatic cancer activity. This project is utilizing both NMR and x-ray crystallographic techniques in developing new inhibitors from these initial hits; c) x-ray structure information was produced for several inhibitors bound to the drug- binding pocket of P-glycoprotein, one of the multi-drug resistance transporters that often become over-active in cancer cells causing resistance to chemotherapy.

分子分析/翻译组 结构生物学共享因子（SBSF） 摘要 结构生物学共享设施（SBSF）为CCC成员提供关键的生物物理设施 包括：1）X射线晶体学数据收集（通过内部X射线系统和专用访问两个 通过东南合作访问小组（SERCAT）的成员资格， 阿贡同步加速器设施; 2）用于水和膜的高通量纳米结晶服务 蛋白质，3）850 MHz至300 MHz范围内的核磁共振（NMR）仪器，以及4） 生物物理测量，包括高通量差示扫描和等温微量热仪。 除了提供最先进的仪器外，SBSF还支持癌症中心 成员通过服务和咨询广泛的结构生物学项目，包括：1） 不同蛋白质、蛋白质-蛋白质和蛋白质-配体复合物的结构测定 癌症; 2）化合物库的基于结构的虚拟筛选; 3）一般药物发现研究 包括基于结构的化学合成; 4）基于片段的新抑制剂设计; 5） 通过NMR和晶体学的化合物库; 6）NMR-代谢组学在癌症研究中的应用， 和膜蛋白作为药物靶点。SBSF与亚拉巴马药物发现中心密切合作 联盟（ADDA），以支持CCC成员的研究工作，开发新药，以治疗多种 癌症的形式。在过去的资助期间，该基金用于支持基础和翻译 研究为105个用户，其中78个是CCC成员，NIH资助超过6000万美元。SBSF使用 导致了50多种不同的新蛋白质结构发表在各种期刊上，包括《科学》， PNAS，生物化学，JBC，JMB，细胞生物学，分子药理学，生物技术趋势，Acta-D， ACTA-F和结构。通过共享设施增加的价值的例子包括： 20维甲酸X受体RXR的X射线结构，RXR是一种与乳腺癌和皮肤T细胞相关的蛋白质。 淋巴瘤一种临床候选药物目前正在NCI进行人体1b期B试验; B）新Src的鉴定 靶向Src/钙调蛋白相互作用并表现出抗胰腺癌的激酶抑制剂（初始命中） 活动该项目利用核磁共振和X射线晶体学技术开发新的抑制剂 从这些初始命中; c）产生与药物结合的几种抑制剂的X射线结构信息， P-糖蛋白的结合口袋，多药耐药转运蛋白之一，往往成为过度活跃， 癌细胞对化疗产生耐药性。