Critical role of desolvation in the binding of 20-hydroxyecdysone to the ecdysone receptor
Critical role of desolvation in the binding of 20-hydroxyecdysone to the ecdysone receptor
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DOI：
10.1074/jbc.m705559200
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发表时间：
2007-11-09
影响因子：
4.8
通讯作者：
Billas, Isabelle M. L.
中科院分区：
文献类型：
--
作者：
Browning, Christopher;Martin, Elyette;Billas, Isabelle M. L.
昆虫类固醇激素 20-羟基蜕皮激素 (20E) 与其由蜕皮激素受体 (EcR) 和 Ultraspiracle (USP) 组成的同源核受体结合，并触发主要的发育转变，特别是蜕皮和变态。我们以 2.4 A 分辨率展示了 EcR/USP 与 20E 复合物的配体结合结构域的晶体结构，并将其与已发表的与松甾酮 A (ponA) 结合的 EcR/USP 结构进行比较。 ponA 本质上与 20E 相同，但缺少 20E 的 25-OH 基团。 20E 结合的 EcR 的结构表明，与 ponA 结合的受体相比，形成了额外的氢键，但矛盾的是，ponA 对 EcR 的亲和力明显高于 20E。基于对接和自由能方法的理论研究为理解 20E 和 ponA 之间的结合亲和力差异提供了理论基础。计算结果表明，与 ponA 相比，20E 的 25-OH 产生的额外氢键所带来的有利贡献被其更大的去溶剂成本所抵消。进一步将 25-OH 对结合亲和力的贡献与 20-和 22-OH 基团的贡献进行比较。事实上，缺乏 20- 或 22-OH 基团的配体与 EcR 的结合不如 20E，这一效果与 ponA 观察到的效果相反。结果表明，它们各自对受体-配体复合物稳定性的贡献主要在于它们对溶剂化/去溶剂化的不同贡献。总之，这些数据证明了配体去溶剂化在确定结合亲和力方面的关键作用，对激素与其同源核受体的结合具有一般意义。
The insect steroid hormone 20-hydroxyecdysone (20E) binds to its cognate nuclear receptor composed of the ecdysone receptor (EcR) and Ultraspiracle (USP) and triggers the main developmental transitions, in particular molting and metamorphosis. We present the crystal structure of the ligand-binding domains of EcR/USP in complex with 20E at 2.4 A resolution and compare it with published structures of EcR/USP bound to ponasterone A (ponA). ponA is essentially identical to 20E but lacks the 25-OH group of 20E. The structure of 20E-bound EcR indicates that an additional hydrogen bond is formed compared with the ponA-bound receptor, yet, paradoxically, ponA has a significantly higher affinity for EcR than 20E. Theoretical studies based on docking and free energy methods lead to a rationale for understanding the difference in binding affinities between 20E and ponA. Results of the calculations indicate that the favorable contribution from the extra H-bond made by 25-OH of 20E is counterbalanced by its larger desolvation cost compared with that of ponA. The contribution of 25-OH to the binding affinity is further compared with those of 20- and 22-OH groups. Ligands that lack the 20- or 22-OH group are indeed known to bind less favorably to EcR than 20E, an effect opposite to that observed for ponA. The results indicate that their respective contributions to receptor-ligand complex stability reside mostly in their different contributions to solvation/desolvation. Together, the data demonstrate the critical role of ligand desolvation in determining binding affinity, with general implications for the binding of hormones to their cognate nuclear receptors.