Journal Article

Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase

Sharma, Nandini, French, Jarrod B., Zhou, Weijie

2026

Overview

Purine nucleotides are ubiquitous molecules essential for all life. The de novo biosynthesis of purines is a metabolic dependency that is frequently reprogrammed in cancers and is a well-established target for chemotherapies, immune modulation and antivirals. Here, we report cryo-electron microscopy structures of the multi-domain human phosphoribosylformylglycinamidine synthase, a central purine biosynthetic enzyme and foundational feature of the purinosome metabolon. These data capture, the proposed iminophosphate intermediate and provide the structural elucidation of an ammonia channel connecting the active sites of the glutaminase and synthase domains. Analysis of this series of structures and the accompanying biochemical data also reveal the molecular features and transient conformational changes that underlie allosteric regulation and catalytic coupling of the domains. This data resolves several longstanding mechanistic questions about this enzyme class and provides a strong foundation for therapeutic development. Here, the authors present structural snapshots of multiple distinct states of the enzyme phosphoribosylformylglycinamidine synthase, describing an allosteric mechanism that regulates transient intraprotein channel formation in this central purine metabolic protein.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/45/173 / 631/45/607/1164 / 631/535/1258/1259 / Allosteric properties / Allosteric Regulation / Ammonia / Antiviral agents / Biosynthesis / Cancer / Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor - chemistry / Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor - metabolism / Catalytic Domain / Chromatography / Coupling / Cryoelectron Microscopy / Data capture / Drug development / Electron microscopy / Energy storage / Enzyme kinetics / Glutaminase / Humanities and Social Sciences / Humans / Immunomodulation / Ligands / Metabolism / Models, Molecular / multidisciplinary / Nucleotides / Phosphoribosylformylglycinamidine synthase / Physiology / Prokaryotes / Protein Conformation / Proteins / Purines / Science / Science (multidisciplinary)