title: Allosteric pathways in imidazole glycerol phosphate synthase.
abstract: Protein allosteric pathways are investigated in the imidazole glycerol phosphate synthase heterodimer in an effort to elucidate how the effector (PRFAR, N'-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide) activates glutaminase catalysis at a distance of 25 Å from the glutamine-binding site. We apply solution NMR techniques and community analysis of dynamical networks, based on mutual information of correlated protein motions in the active and inactive enzymes. We find evidence that the allosteric pathways in the PRFAR bound enzyme involve conserved residues that correlate motion of the PRFAR binding loop to motion at the protein-protein interface, and ultimately at the glutaminase active site. The imidazole glycerol phosphate synthase bienzyme is an important branch point for the histidine and nucleotide biosynthetic pathways and represents a potential therapeutic target against microbes. The proposed allosteric mechanism and the underlying allosteric pathways provide fundamental insights for the design of new allosteric drugs and/or alternative herbicides.
authors.affiliation: Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8107, USA. ivan.rivalta@yale.edu
authors.forename: Ivan
authors.initials: I
authors.lastname: Rivalta
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Sultan
authors.forename: Ning-Shiuan
authors.initials: NS
authors.lastname: Lee
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Manley
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Loria
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation; D000495:Allosteric Site; D000619:Aminohydrolases / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012265:Ribonucleotides / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D020124:Thermotoga maritima / Q000201:enzymology* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007093:Imidazoles; D021122:Protein Subunits; D012265:Ribonucleotides; C081348:N(1)-((5'-phosphoribulosyl)formimino)-5-aminoimidazo-4-carboxamide ribonucleotide; C087227:imidazole glycerol phosphate synthase; D000619:Aminohydrolases