title: Comparative study of structural models of Leishmania donovani and human GDP-mannose pyrophosphorylases.
abstract: Leishmania is the parasite responsible for the neglected disease leishmaniasis. Its virulence and survival require biosynthesis of glycoconjugates, whose guanosine diphospho-d-mannose pyrophosphorylase (GDP-MP) is a key player. However, experimentally resolved structures of this enzyme are still lacking. We herein propose structural models of the GDP-MP from human and Leishmania donovani. Based on a multiple sequences alignment, the models were built with MODELLER and then carefully refined with all atom molecular dynamics simulations in explicit solvent. Their quality was evaluated against several standard criteria, including their ability to bind GDP-mannose assessed by redocking calculations. Special attention was given in this study to interactions of the catalytic site residues with the enzyme substrate and competitive inhibitors, opening the perspective of medicinal chemistry developments.
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Daligaux
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Linh
authors.initials: L
authors.lastname: Tran
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Cavé
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pomel
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: tap.ha-duong@u-psud.fr.
authors.forename: Tâp
authors.initials: T
authors.lastname: Ha-Duong
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry; D006155:Guanosine Diphosphate Mannose / Q000378:metabolism; D006801:Humans; D007893:Leishmania donovani / Q000201:enzymology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D004791:Enzyme Inhibitors; D006155:Guanosine Diphosphate Mannose; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase
keywords: GDP-MP; Homology modeling; Interaction enzyme-ligand; Molecular dynamics simulation; Multiple alignment; Quality assessment