Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, USA.
Nat Struct Mol Biol. 2010 Sep;17(9):1102-8. doi: 10.1038/nsmb.1887. Epub 2010 Aug 22.
The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands.
植物激素脱落酸（ABA）通过十四家族的 PYR/PYL 受体发挥作用，这些受体是通过对吡喃并[2,3-d]嘧啶（pyrabactin）的抗性来鉴定的，吡喃并[2,3-d]嘧啶是一种抑制种子萌发的合成抑制剂。ABA 激活这些受体以抑制 2C 型蛋白磷酸酶，如 ABI1，但仍不清楚这些受体是否可以被拮抗。在这里，我们证明吡喃并[2,3-d]嘧啶是 PYR1 和 PYL1 的激动剂，但出人意料的是，它是 PYL2 的拮抗剂。PYL2-pyrabactin 和 PYL1-pyrabactin-ABI1 复合物的晶体结构揭示了负责受体选择性激活和抑制的机制，这使我们能够设计突变，将 PYL1 转化为吡喃并[2,3-d]嘧啶抑制受体，将 PYL2 转化为吡喃并[2,3-d]嘧啶激活受体，并鉴定新的基于吡喃并[2,3-d]嘧啶的 ABA 受体激动剂。总之，我们的结果确立了 ABA 受体拮抗作用的新概念，阐明了其潜在机制，并为发现新型 ABA 受体配体提供了合理的框架。
