Jacobs Francois J F, Helliwell John R, Brink Alice
Department of Chemistry, University of the Free State, Nelson Mandela Drive, Bloemfontein, 9301, South Africa.
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.
IUCrJ. 2024 May 1;11(Pt 3):359-373. doi: 10.1107/S2052252524002598.
Metal-based complexes with their unique chemical properties, including multiple oxidation states, radio-nuclear capabilities and various coordination geometries yield value as potential pharmaceuticals. Understanding the interactions between metals and biological systems will prove key for site-specific coordination of new metal-based lead compounds. This study merges the concepts of target coordination with fragment-based drug methodologies, supported by varying the anomalous scattering of rhenium along with infrared spectroscopy, and has identified rhenium metal sites bound covalently with two amino acid types within the model protein. A time-based series of lysozyme-rhenium-imidazole (HEWL-Re-Imi) crystals was analysed systematically over a span of 38 weeks. The main rhenium covalent coordination is observed at His15, Asp101 and Asp119. Weak (i.e. noncovalent) interactions are observed at other aspartic, asparagine, proline, tyrosine and tryptophan side chains. Detailed bond distance comparisons, including precision estimates, are reported, utilizing the diffraction precision index supplemented with small-molecule data from the Cambridge Structural Database. Key findings include changes in the protein structure induced at the rhenium metal binding site, not observed in similar metal-free structures. The binding sites are typically found along the solvent-channel-accessible protein surface. The three primary covalent metal binding sites are consistent throughout the time series, whereas binding to neighbouring amino acid residues changes through the time series. Co-crystallization was used, consistently yielding crystals four days after setup. After crystal formation, soaking of the compound into the crystal over 38 weeks is continued and explains these structural adjustments. It is the covalent bond stability at the three sites, their proximity to the solvent channel and the movement of residues to accommodate the metal that are important, and may prove useful for future radiopharmaceutical development including target modification.
具有独特化学性质的金属基配合物，包括多种氧化态、放射性核能力和各种配位几何结构，具有作为潜在药物的价值。了解金属与生物系统之间的相互作用将证明是新的金属基先导化合物进行位点特异性配位的关键。本研究将目标配位概念与基于片段的药物方法相结合，通过改变铼的反常散射以及红外光谱进行支持，并已确定铼金属位点与模型蛋白内的两种氨基酸类型共价结合。在38周的时间跨度内，对一系列基于时间的溶菌酶 - 铼 - 咪唑（HEWL-Re-Imi）晶体进行了系统分析。主要的铼共价配位在His15、Asp101和Asp119处观察到。在其他天冬氨酸、天冬酰胺、脯氨酸、酪氨酸和色氨酸侧链处观察到弱（即非共价）相互作用。利用衍射精度指数并补充来自剑桥结构数据库的小分子数据，报告了详细的键长比较，包括精度估计。主要发现包括铼金属结合位点处诱导的蛋白质结构变化，这在类似的无金属结构中未观察到。结合位点通常沿着溶剂通道可及的蛋白质表面发现。三个主要的共价金属结合位点在整个时间序列中是一致的，而与相邻氨基酸残基的结合在时间序列中发生变化。使用共结晶，在设置后四天始终产生晶体。晶体形成后，在38周内将化合物浸泡到晶体中，并解释了这些结构调整。三个位点处的共价键稳定性、它们与溶剂通道的接近程度以及残基为容纳金属而发生的移动是重要的，并且可能对包括靶点修饰在内的未来放射性药物开发有用。
