Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK.
Nat Chem Biol. 2021 Dec;17(12):1245-1261. doi: 10.1038/s41589-021-00883-7. Epub 2021 Nov 1.
Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cβ-Bγ bond formation provides mild, direct, site-selective access to the minimally sized residue boronoalanine (Bal) in proteins. Precise anchoring of boron within complex biomolecular systems allows dative bond-mediated, site-dependent protein Lewis acid-base-pairing (LABP) by Bal. Dynamic protein-LABP creates tunable inter- and intramolecular ligand-host interactions, while reactive protein-LABP reveals reactively accessible sites through migratory boron-to-oxygen Cβ-Oγ covalent bond formation. These modes of dative bonding can also generate de novo function, such as control of thermo- and proteolytic stability in a target protein, or observation of transient structural features via chemical exchange. These results indicate that controlled insertion of boron facilitates stability modulation, structure determination, de novo binding activities and redox-responsive 'mutation'.
硼在蛋白质中不存在，但却是一种必需的微量元素。它具有独特的键合方式，可以扩展生物功能，包括路易斯酸的模式，而这些模式在生命的典型元素中是不存在的。在这里，我们展示了翻译后 Cβ-Bγ 键的形成可以提供温和、直接、位点选择性的方法，用于在蛋白质中引入最小尺寸的硼烷丙氨酸（Bal）残基。硼在复杂生物分子系统中的精确定位允许通过 Bal 进行介宾键介导的、位点依赖的蛋白质路易斯酸碱对（LABP）。动态蛋白质-LABP 可以创建可调谐的分子间和分子内配体-宿主相互作用，而反应性蛋白质-LABP 通过迁移的硼-氧 Cβ-Oγ 共价键形成来揭示可反应的活性位点。这些配位键的模式也可以产生新的功能，例如控制靶蛋白的热稳定性和蛋白酶稳定性，或通过化学交换观察瞬态结构特征。这些结果表明，硼的可控插入有助于调节稳定性、确定结构、产生新的结合活性和氧化还原响应的“突变”。
