Allosteric pathways in imidazole glycerol phosphate synthase

Area of Science:

• Biochemistry
• Structural Biology
• Enzyme Kinetics

Background:

• Imidazole glycerol phosphate synthase (IGPS) is crucial for histidine and nucleotide biosynthesis.
• Understanding allosteric regulation in IGPS is key for targeting microbial pathways.

Purpose of the Study:

• To elucidate the allosteric mechanism of IGPS activation by the effector PRFAR.
• To identify the protein allosteric pathways connecting effector binding to remote catalytic sites.

Main Methods:

• Solution Nuclear Magnetic Resonance (NMR) spectroscopy.
• Community analysis of dynamical networks using mutual information of protein motions.

Main Results:

• Identified conserved residues forming allosteric pathways in PRFAR-bound IGPS.
• Demonstrated correlation of motion between the PRFAR binding loop, protein-protein interface, and glutaminase active site.
• Showcased allosteric activation of glutaminase catalysis at a distance of 25 Å.

Conclusions:

• The identified allosteric pathways provide a mechanistic basis for IGPS regulation.
• These findings offer fundamental insights for designing novel allosteric drugs and herbicides targeting microbial pathways.