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Altering the allosteric pathway in IGPS suppresses millisecond motions and catalytic activity.

Proc. Natl. Acad. Sci. U.S.A.2017 Apr 25;114(17):E3414-E3423. Epub 2017 Apr 10
George P Lisi 1 , Kyle W East 1 , Victor S Batista 1 , J Patrick Loria 2
George P Lisi 1 , Kyle W East 1 , Victor S Batista 1 , J Patrick Loria 2

[No authors listed]

Author information
  • 1 Department of Chemistry, Yale University, New Haven, CT 06520.
  • 2 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.

摘要


-[(5'-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (PRFAR). The allosteric mechanism of IGPS is reliant on millisecond conformational motions for efficient catalysis. We engineered four mutants of IGPS designed to disrupt millisecond motions and allosteric coupling to identify regions that are critical to IGPS function. Multiple-quantum Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion experiments and NMR chemical shift titrations reveal diminished enzyme flexibility and a reshaping of the allosteric connectivity in each mutant construct, respectively. The functional relevance of the observed motional quenching is confirmed by significant reductions in glutaminase kinetic activity and allosteric ligand binding affinity. This work presents relevant conclusions toward the control of protein allostery and design of unique allosteric sites for potential enzyme inhibitors with regulatory or therapeutic benefit.

KEYWORDS: NMR, allostery, community networks, millisecond motions