8DBJ

Human PRPS1 with Phosphate, ATP, and R5P; Filament Interface

Summary for 8DBJ

• Entry DOI: 10.2210/pdb8dbj/pdb
• EMDB information: 27286
• Descriptor: Ribose-phosphate pyrophosphokinase 1, ADENOSINE-5'-TRIPHOSPHATE, 5-O-phosphono-alpha-D-ribofuranose, ... (6 entities in total)
• Functional Keywords: phosphoribosyl pyrophosphate synthetase, atp and r5p substrates, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 12
• Total formula weight: 428591.92

Authors

Hvorecny, K.L.,Kollman, J.M. (deposition date: 2022-06-14, release date: 2023-02-15, Last modification date: 2024-06-12)

Primary citation

Hvorecny, K.L.,Hargett, K.,Quispe, J.D.,Kollman, J.M.
Human PRPS1 filaments stabilize allosteric sites to regulate activity.
Nat.Struct.Mol.Biol., 30:391-402, 2023

PubMed Abstract: The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here we determine structures of human PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms.

PubMed: 36747094
DOI: 10.1038/s41594-023-00921-z

Experimental method

ELECTRON MICROSCOPY (2 Å)