Institute of General, Inorganic and Theoretical Chemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
J Am Chem Soc. 2010 Aug 4;132(30):10330-7. doi: 10.1021/ja909908y.
Protein-protein interfaces have crucial functions in many biological processes. The large interaction areas of such interfaces show complex interaction motifs. Even more challenging is the understanding of (multi)specificity in protein-protein binding. Many proteins can bind several partners to mediate their function. A perfect paradigm to study such multispecific protein-protein interfaces are snake venom metalloproteases (SVMPs). Inherently, they bind to a variety of basement membrane proteins of capillaries, hydrolyze them, and induce profuse bleeding. However, despite having a high sequence homology, some SVMPs show a strong hemorrhagic activity, while others are (almost) inactive. We present computer simulations indicating that the activity to induce hemorrhage, and thus the capability to bind the potential reaction partners, is related to the backbone flexibility in a certain surface region. A subtle interplay between flexibility and rigidity of two loops seems to be the prerequisite for the proteins to carry out their damaging function. Presumably, a significant alteration in the backbone dynamics makes the difference between SVMPs that induce hemorrhage and the inactive ones.
蛋白质-蛋白质界面在许多生物过程中具有关键功能。这些界面的大相互作用区域显示出复杂的相互作用模式。更具挑战性的是理解蛋白质-蛋白质结合的（多）特异性。许多蛋白质可以结合几个伴侣来介导它们的功能。研究这种多特异性蛋白质-蛋白质界面的完美范例是蛇毒金属蛋白酶 (SVMPs)。它们本质上与毛细血管的各种基底膜蛋白结合，水解它们，并诱导大量出血。然而，尽管具有很高的序列同源性，但一些 SVMP 表现出强烈的出血活性，而其他 SVMP 则几乎没有活性。我们提出了计算机模拟，表明诱导出血的活性，从而与潜在反应伙伴结合的能力，与特定表面区域中的骨架灵活性有关。两个环之间的柔韧性和刚性之间的微妙相互作用似乎是蛋白质发挥其破坏功能的前提。据推测，骨架动力学的显著改变使得引起出血的 SVMP 与不活跃的 SVMP 之间产生了差异。
