title: Conformational Dynamics, Ligand Binding and Effects of Mutations in NirE an S-Adenosyl-L-Methionine Dependent Methyltransferase.
abstract: Heme d1, a vital tetrapyrrol involved in the denitrification processes is synthesized from its precursor molecule precorrin-2 in a chemical reaction catalysed by an S-adenosyl-L-methionine (SAM) dependent Methyltransferase (NirE). The NirE enzyme catalyses the transfer of a methyl group from the SAM to uroporphyrinogen III and serves as a novel potential drug target for the pharmaceutical industry. An important insight into the structure-activity relationships of NirE has been revealed by elucidating its crystal structure, but there is still no understanding about how conformational flexibility influences structure, cofactor and substrate binding by the enzyme as well as the structural effects of mutations of residues involved in binding and catalysis. In order to provide this missing but very important information we performed a comprehensive atomistic molecular dynamics study which revealed that i) the binding of the substrate contributes to the stabilization of the structure of the full complex; ii) conformational changes influence the orientation of the pyrrole rings in the substrate, iii) more open conformation of enzyme active site to accommodate the substrate as an outcome of conformational motions; and iv) the mutations of binding and active site residues lead to sensitive structural changes which influence binding and catalysis.
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom.
authors.forename: Warispreet
authors.initials: W
authors.lastname: Singh
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom.
authors.forename: Tatyana G
authors.initials: TG
authors.lastname: Karabencheva-Christova
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Black
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Ainsley
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom.
authors.forename: Lynn
authors.initials: L
authors.lastname: Dover
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, United Kingdom.
authors.forename: Christo Z
authors.initials: CZ
authors.lastname: Christov
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008780:Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000235:genetics; D012436:S-Adenosylmethionine / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D012436:S-Adenosylmethionine; D008780:Methyltransferases
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