CRYSTAL STRUCTURE OF SQS1 VERSION 2

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 肌肉收缩需要来自粗肌丝的肌球蛋白头与肌动蛋白（细肌丝的主要成分）的周期性相互作用。我们试图通过获得不同收缩状态下的肌球蛋白分子的快照，以原子的细节来可视化肌球蛋白马达是如何工作的。在过去的几年里，我们已经确定了扇贝肌球蛋白头部的原子结构，在各种各样的弱肌动蛋白结合状态，以及一片肌球蛋白尾部，使分子二聚化。肌球蛋白马达通过与脊椎动物骨骼肌细丝上的肌钙蛋白/原肌球蛋白结合的钙离子来切换Son和Soff。这些结构的一个完整的原子描述，试图了解运动活动是如何控制的。我们现在已经确定了近80%的横纹肌原肌球蛋白分子的原子结构。 为了实现我们的目标，必须完全了解肌肉组成蛋白之间的相互作用。我们的长期目标是获得适合X射线分析的这些蛋白质的复合物。目前，我们手头有肌球蛋白和原肌球蛋白的特殊亚型的晶体，它们的不寻常的性质特别适合于理解肌动蛋白的结合。我们最近结晶，收集中等分辨率的X射线数据，并部分完善的结构的鱿鱼肌球蛋白头，这是第一次显示了严格的肌肉肌球蛋白的强肌动蛋白结合构象。我们还获得了一种非肌肉原肌球蛋白亚型的晶体，它与肌动蛋白的结合比传统的原肌球蛋白紧密得多。 从这些晶体和相关晶体中获得高分辨率的同步加速器数据将是理解这些分子功能所必需的特征的关键一步。许多肌肉疾病是由于肌球蛋白马达、肌动蛋白成分和控制机制的缺陷造成的。我们的研究旨在为基于结构的药物设计提供信息。

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. Muscle contraction requires the cyclic interactions of myosin heads from the thick filaments with actin, the major component of the thin filament. We seek to visualize, in atomic detail, how the myosin motor works by obtaining ¿¿¿¿¿Ssnapshots¿¿¿¿¿¿ of the molecule in different states of contraction. Over the past few years, we have determined the atomic structures of the scallop myosin head in a variety of ¿¿¿¿¿Sweak actin-binding¿¿¿¿¿¿ states, as well as a piece of the myosin tail that dimerizes the molecule. The myosin motor is switched ¿¿¿¿¿Son¿¿¿¿¿¿ and ¿¿¿¿¿Soff¿¿¿¿¿¿ by calcium ions which bind to troponin/tropomyosin on the thin filament in vertebrate skeletal muscles. A complete atomic description of these structures is sought to understand how motor activity is controlled. We have now determined the atomic structure of nearly 80% of the striated muscle tropomyosin molecule. To accomplish our goals, a complete understanding of the interactions between the component proteins of muscle must be obtained. Our long term aim is to obtain complexes of these proteins that are suitable for X-ray analysis. Currently, we have in hand crystals of specific isoforms of myosin and tropomyosin whose unusual properties are especially suited for understanding actin binding. We have recently crystallized, collected medium resolution X-ray data, and partially refined the structure of the squid myosin head, which for the first time has shown the rigor-like strong actin-binding conformation of a muscle myosin. We have also obtained crystals of a non-muscle tropomyosin isoform that binds actin much tighter than conventional tropomyosins. Obtaining high resolution synchrotron data from these and related crystals will be a critical step towards understanding the features of these molecules necessary for their functions. Many muscle diseases are due to defects in the myosin motor, the actin component, and in the control machinery. Our studies aim to establish information for structure-based drug design.