Validating a new model for growth hormone receptor activation

生长激素是治疗侏儒症的重要激素。近年来，生长激素的许多新的治疗应用被发现，特别是与它的合成代谢作用有关。这些包括手术后恢复、骨折愈合增强、克罗恩病、扩张性心肌病、不孕症和衰老。这种激素通过受体发挥这些作用，受体是一种细胞因子受体，类似于许多在调节免疫、炎症、代谢和癌症中重要的受体。原则上，如果我们能发现生长激素受体是如何工作的，这些信息将有助于设计治疗许多免疫和炎症疾病的药物。在目前NHMRC的支持下，我们开发了一个模型来描述生长激素如何在分子水平上激活受体。该模型涉及细胞表面的两个预先相关的受体与激素结合，结果是受体相互旋转，这使得两个附着在细胞内受体上的JAK2信号单位对齐，因此它们可以相互激活。我们可以在没有激素的情况下通过人工旋转来激活受体。这个模型是基于几种技术的预测，但缺乏自转的证据。还有一些问题与受体需要刚性有关，这样扭矩才能传递到细胞中，因为许多人认为膜上没有刚性。我们预测有，但需要证明这一点。这一信息对于设计小型口服活性生长激素模拟物和开发可能对乳腺癌和结肠癌有用的生长激素拮抗剂至关重要。最后，我们有证据表明，受体信号的特异性可以通过突变受体的外部部分来改变（新）。我们相信这可以用来改变生长激素的活性谱，从而减少副作用，通过开发类似物激活一个或另一个途径。

Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.