50S RIBOSOMAL SUBUNIT IN COMPLEX WITH NOVEL INHIBITORS OF PROTEIN SYNTHESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 RIB-X制药公司是一家初创阶段的制药公司，其目标是通过开发针对核糖体的新型抗感染分子来解决细菌对现有抗菌剂的耐药性增加带来的医疗困难。医学上迫切需要绕过细菌中已有的抗生素耐药性机制的新药，许多常见的药物类别，如青霉素和大环内酯类，在世界许多地区具有高水平的社区耐药性。尽管许多抗生素针对细菌生命周期的其他方面，但那些与翻译装置结合的抗生素构成了大多数用途。翻译的核心是核糖体，这是一个2.5MDa的大分子复合体，在所有生物体中唯一催化蛋白质的合成。作为一种普遍而必要的聚合酶，它已经成为许多天然和合成抗生素的靶标。细菌核糖体由一个大的50s(1.5mda)和一个小的30s(1.0mda)亚基组成，每个亚基都有互补的活性。近年来，用X-射线结晶学方法已将海参50S亚基的三维结构解析到2.4？分辨率。为了缩短药物发现过程，我们采用了基于结构的设计策略，利用古生菌Haloarcula marismortui的50S核糖体的高分辨率晶体结构，并与小分子抑制剂复合。考虑到我们的原生和真细菌50S晶体的单位尺寸非常大，我们不仅要使用高强度的同步加速器来进行X射线，还要在亮度、光束准直和探测器尺寸方面使用最佳的光束线。

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. Rib-X Pharmaceuticals, Inc. is an early stage pharmaceutical company whose goal is to address the medical difficulties presented by increasing bacterial resistance against current antibacterial agents by developing novel chemical classes of anti-infective molecules that target the ribosome. The medical need for new drugs that circumvent established antibiotic resistance mechanisms in bacteria is dire, with many common drug classes such as penicillins and macrolides having high levels of community resistance in many parts of the world. Though many antibiotics target other aspects of the bacterial life cycle, those that bind to the translational apparatus constitute a majority of use. The central player in translation is the ribosome, a 2.5MDa macromolecular complex that uniquely catalyzes the synthesis of proteins in all organisms. As a universal and essential polymerase, it has been the target of many antibiotics, both natural and synthetic. Bacterial ribosomes are composed of a large 50S (1.5 MDa) and a small 30S (1.0MDa) subunit each with complementary activities. In recent years, the three-dimensional structure of the 50S subunit from H. marismortui has been solved to 2.4 ¿ resolution using x-ray crystallographic methods. In order to shorten the drug discovery process, we employ a structure-based design strategy that utilizes high resolution crystal structures of the 50S ribosome from the archaeal Haloarcula marismortui, complexed with small molecule inhibitors. Given the very large unit cell dimensions of our archeal and eubacterial 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but also the best beamlines in terms of brightness, beam collimation and detector size.