title: Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets.
abstract: BACKGROUND
  Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition. Exploring GSs PPI could allow for the development of inhibitors selective for specific organisms. Here we map the PPI of three GSs-human (hsGS), maize (zmGS) and Mycobacterium tuberculosis (mtGS)-and unravel new drugable pockets.
  
  
  METHODS
  The PPI binding free energy coming from key residues on three GSs from different organisms were mapped by computational alanine scan mutagenesis, applying a multiple dielectric constant MM-PBSA methodology. The most relevant residues for binding are referred as hot-spots. Drugable pockets on GS were detected with the Fpocket software.
  
  
  CONCLUSIONS
  A total of 23, 19 and 30 hot-spots were identified on hsGS, zmGS and mtGS PPI. Even possessing differences in the hot-spots, hsGS and zmGS PPI are overall very similar. On the other hand, mtGS PPI differs greatly from hsGS and zmGS PPI. A novel drugable pocket was detected on the mtGS PPI. It seems particularly promising for the development of selective anti-tuberculosis drugs given its location on a PPI region that is highly populated with hot-spots and is completely different from the hsGS and zmGS PPIs. Drugs targeting this pockets should be inactive on eukaryotic GS II enzymes.
authors: UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal. cds.moreira@fc.up.pt.
authors: Cátia
authors: C
authors: Moreira
authors: UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal. mjramos@fc.up.pt.
authors: Maria J
authors: MJ
authors: Ramos
authors: UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal. pafernan@fc.up.pt.
authors: Pedro A
authors: PA
authors: Fernandes
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D015195:Drug Design; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping / Q000379:methods*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D003313:Zea mays / Q000737:chemistry / Q000201:enzymology
chemical_list: D054852:Small Molecule Libraries; D005974:Glutamate-Ammonia Ligase
keywords: Mycobacterium tuberculosis; computational alanine scanning mutagenesis; drug discovery; drugable pockets; glutamine synthetase; human; inhibition; maize; protein-protein interactions