title: Promiscuous binding at the crossroads of numerous cancer pathways: insight from the binding of glutaminase interacting protein with glutaminase L.
abstract: The glutaminase interacting protein (GIP) is composed of a single PDZ domain that interacts with a growing list of partner proteins, including glutaminase L, that are involved in a number of cell signaling and cancer pathways. Therefore, GIP makes a good target for structure-based drug design. Here, we report the solution structures of both free GIP and GIP bound to the C-terminal peptide analogue of glutaminase L. This is the first reported nuclear magnetic resonance structure of GIP in a complex with one of its binding partners. Our analysis of both free GIP and GIP in a complex with the glutaminase L peptide provides important insights into how a promiscuous binding domain can have affinity for multiple binding partners. Through a detailed chemical shift perturbation analysis and backbone dynamics studies, we demonstrate here that the binding of the glutaminase L peptide to GIP is an allosteric event. Taken together, the insights reported here lay the groundwork for the future development of a specific inhibitor for GIP.
authors.affiliation: Department of Chemistry and Biochemistry, Auburn University, Alabama 36849, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Zoetewey
authors.forename: Mohiuddin
authors.initials: M
authors.lastname: Ovee
authors.forename: Monimoy
authors.initials: M
authors.lastname: Banerjee
authors.forename: Rajagopalan
authors.initials: R
authors.lastname: Bhaskaran
authors.forename: Smita
authors.initials: S
authors.lastname: Mohanty
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005972:Glutaminase / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D012996:Solutions
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D012996:Solutions; C421249:TAX1BP3 protein, human; D005972:Glutaminase