Structural Biology Shared Facility

结构生物学共享设施

• 批准号: 9895644
• 负责人: William J. Placzek
• 金额: $ 29.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895644
• 关键词: 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; P-Glycoprotein; 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 结构生物学共享设施（SBSF） 抽象的 结构生物学共享设施（SBSF）为CCC成员提供了关键生物物理设施的访问 包括：1）X射线晶体学数据收集（通过内部X射线系统以及专用访问两个 通过成员在东南协作访问团队（SERCAT）的会员身份进行同步光束线 Argonne同步设施； 2）水和膜的高通量纳米结晶服务 蛋白质，3）核磁共振（NMR）仪器范围从850 MHz到300 MHz和4） 生物物理测量值，包括高通量差分扫描和等温微含量计。 除了提供使用最先进的仪器的访问外，SBSF还支持癌症中心 通过服务和咨询成员在各种结构生物学项目中的成员：1） 蛋白质，蛋白质蛋白质和蛋白质配体的结构测定不同 癌症； 2）复合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）基于碎片的新抑制剂设计； 5）筛选 NMR和晶体学的复合库； 6）NMR代谢组学在癌症研究中的应用， 并在膜蛋白上作为药物靶标。 SBSF与阿拉巴马州的药物发现紧密合作 联盟（ADDA）支持CCC成员开发新药物以治疗多重药物的研究工作 癌症的形式。在过去的资金期间，该设施用于支持基本和翻译 对105位用户的研究，其中78位是NIH资金超过6000万美元的CCC成员。 SBSF使用 导致了50多种不同的新型蛋白质结构，这些结构发表在包括科学在内的各种期刊上， PNA，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。通过共享设施添加的增值示例包括：a）确定超过 类维氏X受体RXR的20 X射线结构，一种与乳腺癌和皮肤T细胞有关的蛋白质 淋巴瘤。临床药物候选人目前正在NCI的人类1B试验中； b）新型SRC的识别 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。该项目正在利用NMR和X射线晶体学技术来开发新的抑制剂 从这些最初的命中; c）为与药物结合的几种抑制剂产生X射线结构信息 P-糖蛋白的结合袋，这是多药抗性转运蛋白之一，通常在 癌细胞引起对化学疗法的抗性。