Drug Target Exploitable Structural Features of Adenylyl Cyclase Activity in Schistosoma mansoni

Andreas N. Mbah; Henri L. Kamga; Omotayo R. Awofolu; Raphael D. Isokpehi

doi:10.33393/dti.2012.1378

Authors

Andreas N. Mbah Department of Environmental Sciences, College of Agriculture and Environmental Sciences, University of South Africa, South Africa.
Henri L. Kamga Faculty of Health Sciences, University of Buea, Buea, South West Region, Cameroon.
Omotayo R. Awofolu Department of Environmental Sciences, College of Agriculture and Environmental Sciences, University of South Africa, South Africa.
Raphael D. Isokpehi Center for Bioinformatics & Computational Biology, Department of Biology, Jackson State University, Jackson, MS, USA.

DOI:

https://doi.org/10.33393/dti.2012.1378

Keywords:

adenylyl cyclase pathway, biomarkers, GTP binding, novel drug targets, protein domain interactions, pathway regulation, Schistosoma, switch I, switch II

Abstract

The draft genome sequence of the parasitic flatworm Schistosoma mansoni (S. mansoni), a cause of schistosomiasis, encodes a predicted guanosine triphosphate (GTP) binding protein tagged Smp_059340.1. Smp_059340.1 is predicted to be a member of the G protein alpha-s subunit responsible for regulating adenylyl cyclase activity in S. mansoni and a possible drug target against the parasite. Our structural bioinformatics analyses identified key amino acid residues (Ser53, Thr188, Asp207 and Gly210) in the two molecular switches responsible for cycling the protein between active (GTP bound) and inactive (GDP bound) states. Residue Thr188 is located on Switch I region while Gly210 is located on Switch II region with Switch II longer than Switch I. The Asp207 is located on the G3 box motif and Ser53 is the binding residue for magnesium ion. These findings offer new insights into the dynamic and functional determinants of the Smp_059340.1 protein in regulating the S. mansoni life cycle. The binding interfaces and their residues could be used as starting points for selective modulations of interactions within the pathway using small molecules, peptides or mutagenesis.