A Combined Spectroscopic and Protein Crystallography Study Reveals Protein Interactions of RhI(NHC) Complexes at the Molecular Level
A Combined Spectroscopic and Protein Crystallography Study Reveals Protein Interactions of RhI(NHC) Complexes at the Molecular Level
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DOI：
10.1021/acs.inorgchem.0c02438
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发表时间：
2020-12-07
影响因子：
4.6
通讯作者：
Metzler-Nolte, Nils
中科院分区：
文献类型：
--
作者：
Daubit, Isabelle M.;Sullivan, Matthew P.;Metzler-Nolte, Nils
虽然目前在抗癌研究中研究的大多数Rh- n -杂环碳（NHC）配合物含有Rh（III）金属中心，但越来越多的研究集中在含有Rh(I)中心的方形平面[RhCl(COD)(NHC)]（其中COD = 1,5-环二烯）的细胞毒性活性和作用方式上。硫氧还蛋白还原酶（TrxR）和蛋白白蛋白被认为是潜在的靶点，但在蛋白质相互作用下发生的分子过程仍然难以捉摸。本文报道了肽偶联及其非偶联亲本[RhCl(COD)(NHC)]复合物的制备，深入研究了它们在溶液中的稳定性，并对蛋白质相互作用进行了晶体学研究。有机钠化合物在水溶液中COD配体损失快，NHC配体损失慢。这些配体交换反应反映在以蛋清溶菌酶（HEWL）为模型蛋白的单晶x射线晶体学研究中。在用氨基酸功能化的[RhCl(COD)(NHC)]复合物处理HEWL后，在His15孵育7天后和Lys33孵育4周后，发现了两种不同的铑加合物。在这两种情况下，COD和氯基配体都被水和/或羟基配体取代。虽然组氨酸（His）加合物也表明NHC配体的缺失，但赖氨酸（Lys）加合物保留了由氨基酸l-组氨酸衍生的NHC核心。在这两种情况下，金属中心的八面体配位环境表明氧化成Rh（III）。这项研究首次揭示了Rh(I)（NHC）复合物与蛋白质在分子水平上的相互作用。
While most Rh-N-heterocyclic carbene (NHC) complexes currently investigated in anticancer research contain a Rh(III) metal center, an increasing amount of research is focusing on the cytotoxic activity and mode of action of square-planar [RhCl(COD)(NHC)] (where COD = 1,5-cyclooctadiene) which contains a Rh(I) center. The enzyme thioredoxin reductase (TrxR) and the protein albumin have been proposed as potential targets, but the molecular processes taking place upon protein interaction remain elusive. Herein, we report the preparation of peptide-conjugated and its nonconjugated parent [RhCl(COD)(NHC)] complexes, an in-depth investigation of both their stability in solution, and a crystallographic study of protein interaction. The organorhodium compounds showed a rapid loss of the COD ligand and slow loss of the NHC ligand in aqueous solution. These ligand exchange reactions were reflected in studies on the interaction with hen egg white lysozyme (HEWL) as a model protein in single-crystal X-ray crystallographic investigations. Upon treatment of HEWL with an amino acid functionalized [RhCl(COD)(NHC)] complex, two distinct rhodium adducts were found initially after 7 d of incubation at His15 and after 4 weeks also at Lys33. In both cases, the COD and chlorido ligands had been substituted with aqua and/or hydroxido ligands. While the histidine (His) adduct also indicated a loss of the NHC ligand, the lysine (Lys) adduct retained the NHC core derived from the amino acid l-histidine. In either case, an octahedral coordination environment of the metal center indicates oxidation to Rh(III). This investigation gives the first insight on the interaction of Rh(I)(NHC) complexes and proteins at the molecular level.