Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Proc Natl Acad Sci U S A. 2022 Mar 1;119(9). doi: 10.1073/pnas.2122105119.
As natural chemokine inhibitors, evasin proteins produced in tick saliva are potential therapeutic agents for numerous inflammatory diseases. Engineering evasins to block the desired chemokines and avoid off-target side effects requires structural understanding of their target selectivity. Structures of the class A evasin EVA-P974 bound to human CC chemokine ligands 7 and 17 (CCL7 and CCL17) and to a CCL8-CCL7 chimera reveal that the specificity of class A evasins for chemokines of the CC subfamily is defined by conserved, rigid backbone-backbone interactions, whereas the preference for a subset of CC chemokines is controlled by side-chain interactions at four hotspots in flexible structural elements. Hotspot mutations alter target preference, enabling inhibition of selected chemokines. The structure of an engineered EVA-P974 bound to CCL2 reveals an underlying molecular mechanism of EVA-P974 target preference. These results provide a structure-based framework for engineering evasins as targeted antiinflammatory therapeutics.
作为天然趋化因子抑制剂，蜱唾液中产生的逃逸蛋白是许多炎症性疾病的潜在治疗药物。为了阻断所需趋化因子并避免脱靶副作用，需要对逃逸蛋白的靶标选择性有结构上的了解。与人类 C 型趋化因子配体 7 和 17（CCL7 和 CCL17）以及 CCL8-CCL7 嵌合体结合的 A 类逃逸蛋白 EVA-P974 的结构揭示，A 类逃逸蛋白对 CC 亚家族趋化因子的特异性是由保守的、刚性的骨架-骨架相互作用定义的，而对 CC 趋化因子亚组的偏好则由灵活结构元件中四个热点处的侧链相互作用控制。热点突变改变了靶标偏好，从而能够抑制选定的趋化因子。与 CCL2 结合的工程化 EVA-P974 的结构揭示了 EVA-P974 靶标偏好的潜在分子机制。这些结果为作为靶向抗炎治疗药物的逃逸蛋白工程提供了基于结构的框架。
