Computational classification of MocR transcriptional regulators into subgroups as a support for experimental and functional characterization.

Stefano Pascarella

doi:10.6026/97320630015151

Abstract

MocR bacterial transcriptional regulators are a subfamily within the GntR family. The MocR proteins possess an N-terminal domain containing the winged Helix-Turn-Helix (wHTH) motif and a C-terminal domain whose architecture is homologous to the fold type-I pyridoxal 5'-phosphate (PLP) dependent enzymes and whose archetypical protein is aspartate aminotransferase (AAT). The ancestor of the fold type-I PLP dependent super-family is considered one of the earliest enzymes. The members of this super-family are the product of evolution which resulted in a diversified protein population able to catalyze a set of reactions on substrates often containing amino groups. The MocR regulators are activators or repressors of gene control within many metabolic pathways often involving PLP enzymes. This diversity implies that MocR specifically responds to different classes of effector molecules. Therefore, it is of interest to compare the AAT domains of MocR from six bacteria phyla. Multi dimensional scaling and cluster analyses suggested that at least three subgroups exist within the population that reflects functional specialization rather than taxonomic origin. The AAT-domains of the three clusters display variable degree of similarity to different fold type-I PLP enzyme families. The results support the hypothesis that independent fusion events generated at least three different MocR subgroups.

Highlights

There are 8.8 million recorded deaths of malignant cancer every year according to WHO data and this number keep on increasing which is a clear indication of the threat this disease poses
Owing to the fact that the development of these small molecule inhibitors is relatively lacking, the present study aims to identify a potential small molecule inhibitor, which binds with PD-L1 with high affinity and can be carried for further trials for the clinical treatment of lung cancer
Protein and ligand Preparation: The protein 3D structure or the crystal structure of the target protein i.e. the PD-L1 dimer was taken from the Protein Data Bank (PDB) with the PBD ID: 5J8O [20]

Summary

Introduction

There are 8.8 million recorded deaths of malignant cancer every year according to WHO data and this number keep on increasing which is a clear indication of the threat this disease poses. Studies in the past decade have confirmed that the immune system displays a variety of mechanisms to combat the growth of cancer cells in the body. In order for the cancer cells to grow and develop, the cells have to find ways to repress these immunological mechanisms. One such mechanism used is altering the expression of co-inhibitory and co-stimulatory articulated molecules [1]. Cancer immunotherapy is increasingly being used in recent clinical treatments in order to overcome tumorinducedimmunosuppression.

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