Sriram Shashikanth M, Banerjee Rajkumar, Kane Ravi S, Kwon Yong Tae
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Chem Biol. 2009 Feb 27;16(2):121-31. doi: 10.1016/j.chembiol.2009.01.012.
Intracellular signaling is often mediated by a family of functionally overlapping signal mediators that contain multiple sites interacting with other proteins or ligands with weak affinity (K(d) > microM). Conjugation of multiple low-affinity ligands into a high-affinity multivalent molecule provides a means to control the entire protein family within a single intracellular pathway. The N-end rule pathway is a ubiquitin (Ub)-dependent proteolytic system where at least four Ub ligases, called N-recognins, have a common domain critical for binding to type 1 (basic) and type 2 (bulky hydrophobic) destabilizing N-terminal residues of substrates as degrons. The recent development of a heterodivalent inhibitor targeting type 1 and type 2 substrate binding sites of the N-recognin family provides new opportunities to manipulate this proteolytic pathway in biochemical and pathophysiological conditions. We overview the N-end rule pathway as an intracellular target for heterodivalent molecules and discuss the basis of thermodynamics and kinetics related to heterodivalent interactions.
细胞内信号传导通常由一类功能重叠的信号介质介导，这些信号介质包含多个与其他蛋白质或配体以弱亲和力（K(d) > microM）相互作用的位点。将多个低亲和力配体缀合成一个高亲和力的多价分子，为在单个细胞内途径中控制整个蛋白质家族提供了一种方法。N端规则途径是一种依赖泛素（Ub）的蛋白水解系统，其中至少有四种Ub连接酶，称为N识别蛋白，具有一个共同结构域，该结构域对于结合作为降解子的底物的1型（碱性）和2型（大体积疏水）不稳定N端残基至关重要。靶向N识别蛋白家族1型和2型底物结合位点的异二价抑制剂的最新进展，为在生化和病理生理条件下操纵这一蛋白水解途径提供了新机会。我们概述了N端规则途径作为异二价分子的细胞内靶点，并讨论了与异二价相互作用相关的热力学和动力学基础。
