Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
J Virol. 2010 Apr;84(7):3189-200. doi: 10.1128/JVI.01964-09. Epub 2010 Jan 13.
The complement regulation protein CD46 is the primary attachment receptor for most species B adenoviruses (Ads). However, significant variability exists in sequence and structure among species B Ads in the CD46-binding regions, correlating with differences in affinity. Here, we report a structure-function analysis of the interaction of the species B Ad21 knob with the two N-terminal repeats SCR1 and SCR2 of CD46, CD46-D2. We have determined the structures of the Ad21 knob in its unliganded form as well as in complex with CD46-D2, and we compare the interactions with those observed for the Ad11 knob-CD46-D2 complex. Surface plasmon resonance measurements demonstrate that the affinity of Ad21 knobs for CD46-D2 is 22-fold lower than that of the Ad11 knob. The superposition of the Ad21 and Ad11 knob structures in complex with CD46-D2 reveals a substantially different binding mode, providing an explanation for the weaker binding affinity of the Ad21 knob for its receptor. A critical difference in both complex structures is that a key interaction point, the DG loop, protrudes more in the Ad21 knob than in the Ad11 knob. Therefore, the protruding DG loop does not allow CD46-D2 to approach the core of the Ad21 knob as closely as in the Ad11 knob-CD46-D2 complex. In addition, the engagement of CD46-D2 induces a conformational change in the DG loop in the Ad21 knob but not in the Ad11 knob. Our results contribute to a more profound understanding of the CD46-binding mechanism of species B Ads and have relevance for the design of more efficient gene delivery vectors.
补体调节蛋白 CD46 是大多数 B 族腺病毒（Ads）的主要附着受体。然而，B 族 Ads 在 CD46 结合区域的序列和结构存在显著差异，这与亲和力的差异相关。在这里，我们报告了 B 族 Ad21 knob 与 CD46 的两个 N 端重复序列 SCR1 和 SCR2（CD46-D2）相互作用的结构功能分析。我们已经确定了未配体结合形式以及与 CD46-D2 复合物形式的 Ad21 knob 的结构，并将其与观察到的 Ad11 knob-CD46-D2 复合物的相互作用进行了比较。表面等离子体共振测量表明，Ad21 knob 与 CD46-D2 的亲和力比 Ad11 knob 低 22 倍。Ad21 和 Ad11 knob 与 CD46-D2 复合物的结构叠加揭示了一种截然不同的结合模式，为 Ad21 knob 与其受体的结合亲和力较弱提供了解释。两种复合物结构的一个关键区别在于，关键相互作用点，DG 环，在 Ad21 knob 中比在 Ad11 knob 中突出更多。因此，与 Ad11 knob-CD46-D2 复合物相比，突出的 DG 环不允许 CD46-D2 如此紧密地接近 Ad21 knob 的核心。此外，CD46-D2 的结合诱导 Ad21 knob 中的 DG 环发生构象变化，但在 Ad11 knob 中则不会。我们的研究结果有助于更深入地了解 B 族 Ads 的 CD46 结合机制，并为设计更有效的基因传递载体提供了依据。
