Molecular Docking of Known Carcinogen 4- (Methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with Cyclin Dependent Kinases towards Its Potential Role in Cell Cycle Perturbation.

S M A Shahid,Mohd Haneef,Mohtashim Lohani,Sumbul Firdaus,Qazi M S Jamal,S.M.A Shahid,Anupam Dhasmana

doi:10.6026/97320630010526

Abstract

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.

Highlights

Cell cycle is controlled by various regulatory proteins for proper cell division
Preparation of receptor- protein structures The 3D structures of check point proteins (CDKs & Cyclins) involved in cell cycle regulation were obtained from PDB (Protein Data Bank) and some other proteins retrieved from MODBASE server Table 1
The residues ARG 150, ASP 151, LEU 152, LYS 153, THR 196, PHE 197, TRP 198, TYR 199, ARG 200, ALA 201, LEU 204, TYR 211, ILE 215 and ALA 219 of CDK8 and ILE 10, VAL 18, ALA 31, LYS 33, VAL 64, PHE 80, GLU 81, PHE 82, LEU 83, HIS 84, GLN 85, ASP 86, LEU 134 and ALA 144 of CDK2 actively participate in molecular interaction with NNK as shown in Table 5

Summary

Introduction

Cell cycle is controlled by various regulatory proteins (check points) for proper cell division. Cyclins bind to CDKs and form CDK-cyclin complex. This complex/s is/are very important for phase progression in cell cycle [3]. The functional activity of that CDK-cyclin complex is induced conformational changes due to phosphorylation in conserved threonine and tyrosine residues of CDKs part. Changes in functioning of CDKs activity to formed Cdk+Cyclin complex, an important part of many cancers, as well as other disease states, generally through elevated and/or inappropriate activation [6]. One of the probable ways of loss of cell cycle control could be disruption of these regulatory proteins CDKs (check points) by a direct interaction with chemical/carcinogen. We investigated the possible molecular interactions between CDKs, cyclins with potent cigarette smoke carcinogen 4(Methylnitrosamino)-1-(3-Pyridyl)-1-butanone (NNK)

Methods

Results

Discussion

Conclusion