Paladino Antonella, Civera Monica, Belvisi Laura, Colombo Giorgio
Istituto di Chimica del Riconoscimento Molecolare CNR, Milan, Italy.
Dipartimento di Chimica, Università degli Studi di Milano, Milan, Italy.
PLoS Comput Biol. 2017 Jan 23;13(1):e1005334. doi: 10.1371/journal.pcbi.1005334. eCollection 2017 Jan.
Understanding how binding events modulate functional motions of multidomain proteins is a major issue in chemical biology. We address several aspects of this problem by analyzing the differential dynamics of αvβ3 integrin bound to wild type (wtFN10, agonist) or high affinity (hFN10, antagonist) mutants of fibronectin. We compare the dynamics of complexes from large-scale domain motions to inter-residue coordinated fluctuations to characterize the distinctive traits of conformational evolution and shed light on the determinants of differential αvβ3 activation induced by different FN sequences. We propose an allosteric model for ligand-based integrin modulation: the conserved integrin binding pocket anchors the ligand, while different residues on the two FN10's act as the drivers that reorganize relevant interaction networks, guiding the shift towards inactive (hFN10-bound) or active states (wtFN10-bound). We discuss the implications of results for the design of integrin inhibitors.
理解结合事件如何调节多结构域蛋白质的功能运动是化学生物学中的一个主要问题。我们通过分析与纤连蛋白野生型（wtFN10，激动剂）或高亲和力（hFN10，拮抗剂）突变体结合的αvβ3整合素的差异动力学，来解决这个问题的几个方面。我们比较了从大规模结构域运动到残基间协同波动的复合物动力学，以表征构象进化的独特特征，并揭示不同FN序列诱导的αvβ3差异激活的决定因素。我们提出了一种基于配体的整合素调节的变构模型：保守的整合素结合口袋锚定配体，而两个FN10上的不同残基作为驱动因素，重新组织相关的相互作用网络，引导向非活性（hFN10结合）或活性状态（wtFN10结合）转变。我们讨论了这些结果对整合素抑制剂设计的意义。
