Paglia Giuliano, Antonini Lorenzo, Cervoni Laura, Ragno Rino, Sabatino Manuela, Minacori Marco, Rubini Elisabetta, Altieri Fabio
Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Rome Center for Molecular Design, Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Biomedicines. 2021 Oct 25;9(11):1533. doi: 10.3390/biomedicines9111533.
In a previous work, it was shown that punicalagin, an active ingredient of pomegranate, is able to bind to PDIA3 and inhibit its disulfide reductase activity. Here we provide evidence that punicalagin can also bind to PDIA1, the main expressed form of protein disulfide isomerase (PDI). In this comparative study, the affinity and the effect of punicalagin binding on each protein were evaluated, and a computational approach was used to identify putative binding sites. Punicalagin binds to either PDIA1 or PDIA3 with a similar affinity, but the inhibition efficacy on protein reductase activity is higher for PDIA3. Additionally, punicalagin differently affects the thermal denaturation profile of both proteins. Molecular docking and molecular dynamics simulations led to propose a punicalagin binding mode on PDIA1 and PDIA3, identifying the binding sites at the redox domains in two different pockets, suggesting different effects of punicalagin on proteins' structure. This study provides insights to develop punicalagin-based ligands, to set up a rational design for PDIA3 selective inhibitors, and to dissect the molecular determinant to modulate the protein activity.
在之前的一项研究中，已表明石榴的活性成分石榴皮素能够与PDIA3结合并抑制其二硫键还原酶活性。在此，我们提供证据表明石榴皮素还能与蛋白质二硫键异构酶（PDI）的主要表达形式PDIA1结合。在这项比较研究中，评估了石榴皮素与每种蛋白质结合的亲和力和效果，并采用计算方法来确定假定的结合位点。石榴皮素以相似的亲和力与PDIA1或PDIA3结合，但对PDIA3的蛋白质还原酶活性的抑制效果更高。此外，石榴皮素对两种蛋白质的热变性曲线有不同影响。分子对接和分子动力学模拟得出了石榴皮素在PDIA1和PDIA3上的结合模式，确定了在两个不同口袋中的氧化还原结构域的结合位点，这表明石榴皮素对蛋白质结构有不同影响。这项研究为开发基于石榴皮素的配体、为PDIA3选择性抑制剂建立合理设计以及剖析调节蛋白质活性的分子决定因素提供了见解。
