9NB3

Cryo-EM structure of quaternary complex of human phosphoribosylglycinamidine synthase with thioester intermediate bound (at glutaminase site) and AMPPNP and FGAR (at synthase site).

Summary for 9NB3

• Entry DOI: 10.2210/pdb9nb3/pdb
• EMDB information: 49207
• Descriptor: Phosphoribosylformylglycinamidine synthase, N-(N-FORMYLGLYCYL)-5-O-PHOSPHONO-BETA-D-RIBOFURANOSYLAMINE, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (7 entities in total)
• Functional Keywords: quaternary complex phosphoribosylglycinamidine synthase fgar thioester amppnp, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 149962.31

Authors

Sharma, N.,French, J.B. (deposition date: 2025-02-13, release date: 2026-02-25, Last modification date: 2026-04-08)

Primary citation

Sharma, N.,Zhou, W.,French, J.B.
Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase.
Nat Commun, 17:-, 2026

PubMed Abstract: 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.

PubMed: 41688441
DOI: 10.1038/s41467-026-69423-y

Experimental method

ELECTRON MICROSCOPY (3.19 Å)