title: Dissecting Dynamic Allosteric Pathways Using Chemically Related Small-Molecule Activators.
abstract: The allosteric mechanism of the heterodimeric enzyme imidazole glycerol phosphate synthase was studied in detail with solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. We studied IGPS in complex with a series of allosteric activators corresponding to a large range of catalytic rate enhancements (26- to 4,900-fold), in which ligand binding is entropically driven. Conformational flexibility on the millisecond timescale plays a crucial role in intersubunit communication. Carr-Purcell-Meiboom-Gill relaxation dispersion experiments probing Ile, Leu, and Val methyl groups reveal that the apo- and glutamine-mimicked complexes are static on the millisecond timescale. Domain-wide motions are stimulated in the presence of the allosteric activators. These studies, in conjunction with ligand titrations, demonstrate that the allosteric network is widely dispersed and varies with the identity of the effector. Furthermore, we find that stronger allosteric ligands create more conformational flexibility on the millisecond timescale throughout HisF. This domain-wide loosening leads to maximum catalytic activity.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Lisi
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Manley
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hendrickson
authors.affiliation: École Normale Supérieure de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie UMR 5182, 46, Allée d'Italie, 69364 Lyon Cedex 07, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rivalta
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA. Electronic address: victor.batista@yale.edu.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA. Electronic address: patrick.loria@yale.edu.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Loria
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000619:Aminohydrolases / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D007555:Isoxazoles; D008024:Ligands; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C087227:imidazole glycerol phosphate synthase; D000619:Aminohydrolases; C031143:AICA ribonucleotide; C006303:acivicin