title: Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.
abstract: Microsomal prostaglandin E synthase-1 (mPGES-1) is an essential enzyme involved in a variety of diseases and is the most promising target for the design of next-generation anti-inflammatory drugs. In order to establish a solid structural base, we recently developed a model of mPGES-1 trimer structure by using available crystal structures of both microsomal glutathione transferase-1 (MGST1) and ba3-cytochrome c oxidase as templates. The mPGES-1 trimer model has been used in the present study to examine the detailed binding of mPGES-1 trimer with substrate PGH(2) and cofactor GSH. Results obtained from the computational alanine scanning reveal the contribution of each residue at the protein-ligand interaction interface to the binding affinity, and the computational predictions are supported by the data obtained from the corresponding wet experimental tests. We have also compared our mPGES-1 trimer model with other available 3D models, including an alternative homology model and a low-resolution crystal structure, and found that our mPGES-1 trimer model based on the crystal structures of both MGST1 and ba3-cytochrome c oxidase is more reasonable than the other homology model of mPGES-1 trimer constructed by simply using a low-resolution crystal structure of MGST1 trimer alone as a template. The available low-resolution crystal structure of mPGES-1 trimer represents a closed conformation of the enzyme and thus is not suitable for studying mPGES-1 binding with ligands. Our mPGES-1 trimer model represents a reasonable open conformation of the enzyme and is therefore promising for studying mPGES-1 binding with ligands in future structure-based drug design targeting mPGES-1.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
authors.forename: Adel
authors.initials: A
authors.lastname: Hamza
authors.forename: Min
authors.initials: M
authors.lastname: Tong
authors.forename: Mohamed Diwan M
authors.initials: MD
authors.lastname: AbdulHameed
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.forename: Alan C
authors.initials: AC
authors.lastname: Goren
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Tai
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D000409:Alanine; D055162:Biocatalysis; D003067:Coenzymes / Q000378:metabolism; D003198:Computer Simulation; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D044262:Prostaglandin H2 / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013816:Thermodynamics
chemical_list: D003067:Coenzymes; D044262:Prostaglandin H2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D005978:Glutathione; D000409:Alanine