Structural Studies of Growth Factor Receptor Function

性状（由申请人提供）：表皮生长因子受体 （EGFR）同源物Her-2与其他EGFR家族成员形成异二聚体， 对几种EGF样配体的反应。这些二聚体导致细胞的活化， Her-2的胞质激酶结构域，其通常导致细胞凋亡。 增殖Her-2表达在癌症中经常升高， 乳腺卵巢和肺的肿瘤Her-2激酶的激活， 不适当的二聚化被认为有助于发展， 这些恶性肿瘤的严重程度。逆转Her-2激活的疗法是 因此引起了极大的兴趣，以及针对 Her-2，商品名为赫赛汀，最近被证明是一种有效的治疗方法， 其中Her-2过度表达的乳腺癌的子集。Her-2 过度表达的癌症占175，000例新病例中的约50，000例， 乳腺癌的诊断每年在美国。无原子结构 对于任何EGFR家族成员的细胞外结构域都存在。我们已经成长 629个氨基酸胞外同源二聚体的衍射质量晶体 结构域（ECD）。我们的首要目标是完成 Her-2 ECD表征Her-2二聚体界面，并提供 为解释EGFR家族成员的功能提供分子基础。肽 将检测从二聚体界面发现的Her-2序列衍生的 它们阻断Her-2二聚化的能力，从而潜在地作为先导化合物， 用于开发新的抗癌药物的化合物。我们的第二个目标是 确定Her-1和Her-3的ECD在没有结合的情况下的结构 配体之间的比较提供了基础，以及与不同的EGFR 用结合的配体确定她的ECD结构。我们的第三个目标是确定 Her-2和Her-3ECD的活性信号传导复合物的结构， Neu分化因子（NDF; heregulin）的受体结合域。我们 最终目的是确定Her-1 ECD与EGF的复合物的结构。 这些研究将导致对新的靶向治疗的研究， 人类癌症，并揭示配体特异性和信号的原子细节 EGFR家族中的基因。

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.