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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.

SUBMITTER: Lisi GP 

PROVIDER: S-EPMC4938718 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Dissecting Dynamic Allosteric Pathways Using Chemically Related Small-Molecule Activators.

Lisi George P GP   Manley Gregory A GA   Hendrickson Heidi H   Rivalta Ivan I   Batista Victor S VS   Loria J Patrick JP  

Structure (London, England : 1993) 20160526 7


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 communi  ...[more]

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