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Probing Protein-protein Interactions and Druggable Site Identification: Mechanistic Binding Events Between Ubiquitin and Zinc Finger with UFM1-specific Peptidase Domain Protein (ZUFSP)

Author(s):

Mary B. Ajadi, Opeyemi S. Soremekun, Ahmed A Elrashedy, Fisayo A. Olotu, Hezekiel M. Kumalo and Mahmoud E. S. Soliman*   Pages 1 - 8 ( 8 )

Abstract:


Background: Deubiquitinating enzymes (DUBs) protein family have been implicated in some deregulated pathways involved in carcinogenesis such as cell cycle, gene expression, and DNA damage response (DDR). Zinc finger with UFM1-specific peptidase domain protein (ZUFSP) is one of the recently discovered members of the DUBs Objectives: To identify and cross validate the ZUFSP binding site using the bioinformatic tools including SiteMap & Metapocket respectively. To understand the molecular basis of complementary ZUFSP-Ub interaction and associated structural events using MD Simulation Methods: In this study, four binding pockets were predicted, characterized, and cross-validated based on physiochemical features such as site score, druggability score, site volume, and site size. Also, Molecular dynamics simulation technique was employed to determine the impact of ubiquitin-binding on ZUFSP Results: Site 1 with a site score 1.065, Size 102, D scores 1.00, and size volume 261 was predicted to be the most druggable site. Structural studies revealed that upon ubiquitin-binding, the motional movement of ZUFSP was reduced when compared to the unbound ZUFSP. Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub, this orientation enables the formation of a UBD which is very peculiar to ZUFSP. Conclusion: The impact of ubiquitin on ZUFSP movement and the characterization of its predicted druggable site can be targeted in the development of therapeutics

Keywords:

Binding site, ZUFSP, Ubiquitin, Molecular Dynamic Simulation, Deubiquitinating enzymes, Cancer.

Affiliation:

Department of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Howard Campus, Durban 4000, , Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, , Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, , Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, , Department of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Howard Campus, Durban 4000, , Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001



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