Domain Analysis and Structural characterization of Bromodomain 8 (BRD8) -Functional Implications and Importance as a Drug Target in Cancer Research

Author: Ambili Savithri, Sindhu Rani J.A., Asha S. Kumar, Anila L., Maya Madhavan, Sabeena Mustafa and Manju L.

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Abstract

Bromodomains (BRDs) are readers that bind to acetylated lysine residues in chromatin and regulate gene expression. The crystal structure of BRD8 is not elucidated yet. As BRDs play a significant role in cancer, understanding their functional implications is important for drug discovery. The theoretical model is the only reliable technique when there is no crystal structure available. We have investigated the primary and secondary structures of BRD8 (UniProt Id: Q9H0E9|) using the ExPASy (the Expert Protein Analysis System), ProtParam and SOPMA. A model of BRD8 was determined using the template (PDB Id: 3S91) and BLASTP. The stereochemical quality of the model was validated using Ramachandran Plot (97.1% residues in the most favorable region) and ProSA-web (Z score of -5.79). PTM studies show that there are 10 functional sites present in BRD8, of which Protein kinase C and Casein Kinase II sites were abundant. Protein kinase C controls the signaling pathways in proliferation, tumorigenesis and metastasis, whereas Casein Kinase II regulates apoptosis and cell cycle in cancers. We identified three binding pockets in the model. The results from this study show the relevance of BRD8 in cancer research. Functional and structural research can help provide the basis for further studies, which is significant for the pharmaceutical industry as a whole.

Keywords

Bromodomain, BRD8, Molecular modeling, Post-translational modifications, Rampage server, SOPMA, cancer

Conclusion

In line with the fundamental biological concept of “Structure implies the Function”, we felt that it is the need of the hour to do a structural characterisation of BRD8 since no such structural models are currently found in the repository. We constructed a three-dimensional structural model of BRD8 using molecular modelling and the quality and reliability of the constructed model was assessed satisfactorily. Further, we could predict the binding pockets present in the validated model. One limitation of this study is that the role of identified residues should be validated using in silico drug binding and dynamics studies which requires sophisticated software facilities. Screening of combinatorial libraries of small molecules or natural compounds is warranted to shortlist a set of compounds before investigating them using wetlab studies.

References

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How to cite this article

Ambili Savithri, Sindhu Rani J.A., Asha S. Kumar, Anila L., Maya Madhavan, Sabeena Mustafa and Manju L. (2023). Domain Analysis and Structural characterization of Bromodomain 8 (BRD8) -Functional Implications and Importance as a Drug Target in Cancer Research. Biological Forum – An International Journal, 15(5a): 39-51.