Structural Studies of Growth Factor Receptor Function

描述(申请人提供)：表皮生长因子受体 (EGFR)与其他EGFR家族成员的HER-2同源异源二聚体 对几种EGF样配体的反应。这些二聚体导致激活 HER-2的胞浆激活区，通常导致细胞 扩散。HER-2在癌症中的表达经常升高，包括 乳房、卵巢和肺。HER-2激酶的激活通过 不适当的二聚化被认为有助于发展和 这些恶性肿瘤的严重性。逆转HER-2激活的疗法有 因此引起了极大的兴趣，并且抗胞外域的抗体 HER-2，商品名为Herceptin，最近被证明是一种有效的治疗 HER-2在乳腺癌中过度表达的子集。这些是HER-2 在17.5万例新发癌症病例中，过度表达的癌症约占5万例 在美国，每年都会诊断出乳腺癌。没有原子结构 存在于任何EGFR家族成员的胞外区。我们已经成长了 胞外629个氨基酸同源二聚体的衍射性晶体 HER-2的结构域(ECD)。我们的第一个目标是完成晶体结构 HER-2 ECD以表征HER-2二聚体界面并提供 解释EGFR家族成员功能的分子基础。肽类 从二聚体界面上发现的HER-2序列衍生出来的将被测试 它们能够阻止HER-2二聚化，从而潜在地充当铅 用于开发新型抗癌药物的化合物。我们的第二个目标是 HER-1和HER-3在无结合状态下ECDs结构的测定 为不同EGFR之间的比较以及与 她的ECD结构由结合的配体决定。我们的第三个目标是确定 HER-2和HER-3 ECDs活性信号复合体的结构 神经分化因子的受体结合域(NDF；hereglin)。我们的 最终目的是确定HER-1 ECD与EGF的复合体的结构。 这些研究将导致对新的靶向治疗方法的研究 并揭示了配体特异性和信号的原子细节 在EGFR家族中的转导。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) homolog Her-2 forms heterodimers with other EGFR family members in response to several EGF-like ligands. These dimers result in activation of the cytoplasmic kinase domain of Her-2, which typically leads to cell proliferation. Her-2 expression is frequently elevated in cancers including those of the breast, ovaries, and lung. Activation of the Her-2 kinase through inappropriate dimerization is thought to contribute to the development and severity of these malignancies. Therapies that reverse Her-2 activation are thus of great interest, and antibodies against the extracellular domain of Her-2, trade named Herceptin, have recently proven an effective treatment in the subset of breast cancers in which Her-2 is overexpressed. These Her-2 overexpressing cancers account for about 50,000 of the 175,000 new cases of breast cancer diagnosed each year in the United States. No atomic structure exists for the extracellular domain of any EGFR family member. We have grown diffraction-quality crystals of homodimers of the 629 amino acid extracellular domain (ECD) of Her-2. Our first aim is to complete the crystal structure of the Her-2 ECD to characterize the Her-2 dimer interface as well as provide a molecular basis for interpreting the function of EGFR family members. Peptides derived from Her-2 sequences found at the dimer interface will be tested for their ability to block Her-2 dimerization and thus potentially serve as lead compounds for the development of new anti-cancer drugs. Our second aim is to determine the structures of the ECDs of Her-1 and Her-3 in the absence of bound ligand to provide a basis for comparison among different EGFRs as well as with Her ECD structures determined with bound ligand. Our third aim is to determine the structure of an active signaling complex of the Her-2 and Her-3 ECDs with the receptor-binding domain of Neu Differentiation Factor (NDF; heregulin). Our final aim is to determine the structure of a complex of the Her-1 ECD with EGF. These studies will lead to investigation of new target-based therapies for human cancers and reveal the atomic details of ligand specificity and signal transduction in the EGFR family.