title: Modeling of a new tubercular maltosyl transferase, GlgE, study of its binding sites and virtual screening.
abstract: Recently maltosyl transferase of Mycobacterium tuberculosis (mtb GlgE) belonging to α-amylase family has been identified as a potential drug target. Despite its importance, its three dimensional (3D) structure is unavailable. In this study we have modeled its 3D homo-dimeric structure using its homologue in Streptomyces ceolicolor (stp GlgE) as the template. Its monomer consists of five domains and four inserts, out of which two inserts are unique to mtb GlgE. It also has three binding cavities. One primary (pbs) and two secondary (sbs1 and sbs2), with one unique insert appearing within sbs2. Investigation of its homo-dimeric model revealed the presence of a disulphide bridge between Cys-29 of both the chains which is absent in stp GlgE. Virtual screening with known substrates and substrate analogues of α-amylase family proteins indicated better binding of maltose to sbs1 than pbs. Among all computationally screened substrates 3-O-Alpha-D-Glucopyranosyl-D-Fructose (OTU) docked with best binding affinity to pbs. Interaction of known inhibitors of α-amylase family proteins from CHEMBL is also studied. This reveals for the first time the unique 3D structure of mtb GlgE and provides insights into its active sites and substrate binding affinities. This may help in developing new anti-tubercular drugs and its analogues.
authors.affiliation: Machine Intelligence Unit, Indian Statistical Institute, 203 B.T. Road, Kolkata, 700108, India, soumi_t@isical.ac.in.
authors.forename: Soumi
authors.initials: S
authors.lastname: Sengupta
authors.forename: Debjani
authors.initials: D
authors.lastname: Roy
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D005964:Glucosyltransferases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D048372:Streptomyces coelicolor / Q000201:enzymology; D000516:alpha-Amylases / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D005964:Glucosyltransferases; C436710:maltosyltransferase; D000516:alpha-Amylases