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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。Rib-X Pharmaceuticals，Inc.是一家处于早期阶段的制药公司，其目标是通过开发靶向核糖体的新型化学类抗感染分子来解决因增加细菌对当前抗菌剂的抗性而带来的医疗困难。对规避细菌中已建立的抗生素耐药性机制的新药的医疗需求是迫切的，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方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，但与翻译装置结合的抗生素占大多数。翻译的核心是核糖体，一种2.5MDa的大分子复合物，在所有生物体中独特地催化蛋白质的合成。作为一种普遍和必需的聚合酶，它已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50 S（1.5 MDa）和一个小的30 S（1.0 MDa）亚基组成，每个亚基具有互补的活性。近年来，H.使用X射线晶体学方法，marismortui已被解析到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，该策略利用了来自古菌Haloarcula marismortui的50 S核糖体的高分辨率晶体结构，与小分子抑制剂复合。考虑到我们的古细菌和真细菌50 S晶体的非常大的晶胞尺寸，我们不仅要使用高强度的同步加速器X射线源，而且要使用亮度、光束准直和检测器尺寸方面的最佳光束线。

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.