Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Structure. 2012 Apr 4;20(4):688-97. doi: 10.1016/j.str.2012.02.011. Epub 2012 Apr 3.
The discoidin domain receptors, DDR1 and DDR2, are constitutively dimeric receptor tyrosine kinases that are activated by triple-helical collagen. Aberrant DDR signaling contributes to several human pathologies, including many cancers. We have generated monoclonal antibodies (mAbs) that inhibit DDR1 signaling without interfering with collagen binding. The crystal structure of the monomeric DDR1 extracellular region bound to the Fab fragment of mAb 3E3 reveals that the collagen-binding discoidin (DS) domain is tightly associated with the following DS-like domain, which contains the epitopes of all mAbs. A conserved surface patch in the DS domain outside the collagen-binding site is shown to be required for signaling. Thus, the active conformation of the DDR1 dimer involves collagen-induced contacts between the DS domains, in addition to the previously identified association of transmembrane helices. The mAbs likely inhibit signaling by sterically blocking the extracellular association of DDR1 subunits.
盘状结构域受体 DDR1 和 DDR2 是组成型二聚体受体酪氨酸激酶，可被三螺旋胶原激活。异常的 DDR 信号会导致多种人类疾病，包括许多癌症。我们已经生成了单克隆抗体 (mAb)，这些抗体可以抑制 DDR1 信号，而不会干扰胶原蛋白的结合。与 mAb 3E3 的 Fab 片段结合的单体 DDR1 细胞外区域的晶体结构显示，胶原蛋白结合的盘状结构域 (DS) 与以下 DS 样结构域紧密相关，该结构域包含所有 mAb 的表位。DS 结构域内胶原结合位点之外的保守表面斑块表明，其对信号传递是必需的。因此，DDR1 二聚体的活性构象涉及 DS 结构域之间胶原诱导的接触，除了先前确定的跨膜螺旋的关联。这些 mAb 可能通过空间位阻阻止 DDR1 亚基的细胞外缔合来抑制信号传递。
