Structural Biology Shared Facility

分子分析/翻译组 结构生物共享设施(SBSF) 摘要 结构生物学共享设施(SBSF)为CCC成员提供对关键生物物理设施的访问 包括：1)X射线结晶学数据收集(通过内部X射线系统和专门访问两个 通过东南协作访问小组(SERCAT)成员身份的同步加速器束线 Argonne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的核磁共振(核磁共振)仪器和4) 生物物理测量，包括高通量差示扫描和等温微量热计。 除了提供对最先进的仪器的访问，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，范围包括：1) 不同蛋白质、蛋白质-蛋白质和蛋白质-配体络合物的结构测定 癌症；2)基于结构的化合物文库的虚拟筛选；3)药物发现研究 包括基于结构的化学合成；4)基于片段的新型缓蚀剂的设计；5)筛选 核磁共振和结晶学化合物文库；6)核磁共振代谢组学在癌症研究中的应用， 以及作为药物靶点的膜蛋白。SBSF与阿拉巴马州药物发现局密切合作 联盟(ADDA)支持CCC成员开发治疗多发性疾病的新药的研究努力 各种形式的癌症。在过去的筹资期间，该基金被用来支持基本和翻译 对105名用户进行研究，其中78名是美国国立卫生研究院资助超过6000万美元的CCC成员。SBSF使用率 结果在包括《科学》在内的各种期刊上发表了50多种不同的新蛋白质结构， PNAS，生物化学，JBC，JMB，细胞生物学，分子药理学，生物技术趋势，学报-D， Acta-F和结构。通过共享设施增加的价值的例子包括：a)确定多于 维甲酸X受体RXR的20个X射线结构，RXR是一种与乳腺癌和皮肤T细胞有关的蛋白质 淋巴瘤。一种临床候选药物目前正在NCI进行人类1b期试验；b)新的Src的鉴定 针对Src/钙调蛋白相互作用并表现出抗胰腺癌作用的激酶抑制剂(初始HITS) 活动。该项目正在利用核磁共振和x射线结晶学技术开发新的缓蚀剂。 根据这些最初的命中；c)产生了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，这是一种多药耐药转运蛋白，经常在 对化疗产生抗药性的癌细胞。

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.