Haneef Mohd, Lohani Mohtashim, Dhasmana Anupam, Jamal Qazi M S, Shahid S M A, Firdaus Sumbul
Department of Biosciences, Integral University, Lucknow-226026, UP, India.
Department of Bioengineering, Integral University, Lucknow-226026, UP, India.
Bioinformation. 2014 Aug 30;10(8):526-32. doi: 10.6026/97320630010526. eCollection 2014.
Cell cycle is maintained almost all the times and is controlled by various regulatory proteins and their complexes (Cdk+Cyclin) in different phases of interphase (G1, S and G2) and mitosis of cell cycle. A number of mechanisms have been proposed for the initiation and progression of carcinogenesis by abruption in cell cycle process. One of the important features of cancer/carcinogenesis is functional loss of these cell cycle regulatory proteins particularly in CDKs and cyclins. We hypothesize that there is a direct involvement of these cell cycle regulatory proteins not only at the genetic level but also proteins level, during the initiation of carcinogenesis. Therefore, it becomes significant to determine inconsistency in the functioning of regulatory proteins due to interaction with carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Hence, we investigated the interaction efficiency of NNK, against cell cycle regulatory proteins. We found a different value of ΔG (free energy of binding) among the studied proteins ranging between -3.29 to -7.25 kcal/mol was observed. To validate the results, we considered Human Oxy-Hemoglobin at 1.25 Å Resolution, [PDB_ID:1HHO] as a +ve control, (binding energy -6.06 kcal/mol). Finally, the CDK8 (PDB_ID:3RGF) and CDK2 (PDB_ID:3DDP) regulatory proteins showing significantly strong molecular interaction with NNK -7.25 kcal/mol, -6.19 kcal/mol respectively were analyzed in details. In this study we predicted that CDK8 protein fails to form functional complex with its complementary partner cyclin C in presence of NNK. Consequently, inconsistency of functioning in regulatory proteins might lead to the abruption in cell cycle progression; contribute to the loss of cell cycle control and subsequently increasing the possibility of carcinogenesis.
细胞周期几乎一直处于维持状态，并在细胞周期的间期（G1、S和G2期）以及有丝分裂的不同阶段由各种调节蛋白及其复合物（细胞周期蛋白依赖性激酶+细胞周期蛋白）进行调控。关于细胞周期过程中断引发癌症发生及其进展，已经提出了许多机制。癌症/致癌作用的一个重要特征是这些细胞周期调节蛋白功能丧失，尤其是细胞周期蛋白依赖性激酶（CDK）和细胞周期蛋白。我们假设在致癌作用起始过程中，这些细胞周期调节蛋白不仅在基因水平而且在蛋白质水平都有直接参与。因此，确定由于与致癌物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）相互作用导致的调节蛋白功能不一致变得很重要。因此，我们研究了NNK与细胞周期调节蛋白的相互作用效率。我们发现在研究的蛋白质中观察到的结合自由能（ΔG）值不同，范围在-3.29至-7.25千卡/摩尔之间。为了验证结果，我们将分辨率为1.25 Å的人氧合血红蛋白[PDB_ID:1HHO]作为阳性对照（结合能为-6.06千卡/摩尔）。最后，对分别与NNK显示出显著强分子相互作用的细胞周期蛋白依赖性激酶8（CDK8，PDB_ID:3RGF）和细胞周期蛋白依赖性激酶2（CDK2，PDB_ID:3DDP）调节蛋白进行了详细分析，其结合能分别为-7.25千卡/摩尔和-6.19千卡/摩尔。在本研究中，我们预测在存在NNK的情况下，CDK8蛋白无法与其互补伴侣细胞周期蛋白C形成功能复合物。因此，调节蛋白功能的不一致可能导致细胞周期进程中断；导致细胞周期控制丧失，并随后增加致癌的可能性。
