title: Orientation of 1,3-bisphosphoglycerate analogs bound to phosphoglycerate kinase.
abstract: We have previously reported dissociation constants for a range of bisphosphonate analogs of 1,3-bisphospho-D-glyceric acid binding to yeast phosphoglycerate kinase. Data for the unsymmetrical analogs were difficult to interpret because it was not clear in which of the two possible orientations these ligands bound. Here we report a novel NMR method for quantifying orientation preference based on relaxation effects induced by titration with CrADP, which is applied to these ligands. It is shown that all ligands can bind in both orientations but that the driving force for the orientational preference is to put the alpha,alpha-difluoromethanephosphonate group in the "basic patch" (nontransferable phosphate) position. The relevance to the design of phosphoglycerate kinase inhibitors is discussed.
authors.affiliation: Department of Chemistry, Krebs Institute, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors.forename: David L
authors.initials: DL
authors.lastname: Jakeman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ivory
authors.forename: G Michael
authors.initials: GM
authors.lastname: Blackburn
authors.forename: Michael P
authors.initials: MP
authors.lastname: Williamson
mesh_terms: D004164:Diphosphonates / Q000737:chemistry / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010735:Phosphoglycerate Kinase / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology
chemical_list: D004164:Diphosphonates; D010735:Phosphoglycerate Kinase