From the Centenary Institute, National Health and Medical Research Council Clinical Trials Centre, Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia.
From the Centenary Institute, National Health and Medical Research Council Clinical Trials Centre, Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia
J Biol Chem. 2019 Feb 22;294(8):2949-2960. doi: 10.1074/jbc.REV118.005604. Epub 2019 Jan 10.
Protein disulfide bonds link pairs of cysteine residues in polypeptide chains. Many of these bonds serve a purely structural or energetic role, but a growing subset of cleavable disulfide bonds has been shown to control the function of the mature protein in which they reside. These allosteric disulfides and the factors that cleave these bonds are being identified across biological systems and life forms and have been shown to control hemostasis, the immune response, and viral infection in mammals. The discovery of these functional disulfides and a rationale for their facile nature has been aided by the emergence of a conformational signature for allosteric bonds. This post-translational modification mostly occurs extracellularly, making these chemical events prime drug targets. Indeed, a membrane-impermeable inhibitor of one of the cleaving factors is currently being trialed as an antithrombotic agent in cancer patients. Allosteric disulfides are firmly established as a sophisticated means by which a protein's shape and function can be altered; however, the full scope of this biological regulation will not be realized without new tools and techniques to study this regulation and innovative ways of targeting it.
蛋白质中二硫键将多肽链上的半胱氨酸残基连接成对。这些键中的许多仅具有结构或能量作用，但越来越多的可切割二硫键已被证明可以控制其所在成熟蛋白质的功能。这些变构二硫键和切割这些键的因素在整个生物系统和生命形式中被识别出来，并已被证明可以控制哺乳动物的止血、免疫反应和病毒感染。这些功能二硫键的发现以及其易于形成的原理得益于变构键构象特征的出现而得到了促进。这种翻译后修饰主要发生在细胞外，使这些化学事件成为主要的药物靶点。事实上，一种穿透细胞膜的切割因子抑制剂目前正在作为癌症患者的抗血栓药物进行临床试验。变构二硫键已被牢固确立为一种改变蛋白质形状和功能的复杂手段；然而，如果没有研究这种调节的新工具和技术以及针对这种调节的创新方法，这种生物调节的全部范围将无法实现。
