9HG3

Crystal structure of M. smegmatis GMP reductase in complex with GMP and GTP.

Summary for 9HG3

• Entry DOI: 10.2210/pdb9hg3/pdb
• Related: 8RY5
• Descriptor: GMP reductase, GUANOSINE-5'-MONOPHOSPHATE, GUANOSINE-5'-TRIPHOSPHATE (3 entities in total)
• Functional Keywords: gmp reductase, guab1, cbs domain, mycobacterium smegmatis, oxidoreductase
• Biological source: Mycolicibacterium smegmatis
• Total number of polymer chains: 8
• Total formula weight: 421350.68

Authors

Dolezal, M.,Pichova, I. (deposition date: 2024-11-18, release date: 2025-08-27, Last modification date: 2026-04-22)

Primary citation

Dolezal, M.,Knejzlik, Z.,Kouba, T.,Filimonenko, A.,Svachova, H.,Dedola, M.,Klima, M.,Pichova, I.
Structural basis for allosteric regulation of mycobacterial guanosine 5 ́-monophosphate reductase by ATP and GTP.
Nat Commun, 2026

PubMed Abstract: Guanosine 5'-monophosphate reductase (GMPR) is a crucial enzyme in the purine salvage pathway that catalyses the NADPH-dependent conversion of GMP to IMP, thereby contributing to purine nucleotide homeostasis. Mycobacterium smegmatis GMPR (MsmGMPR) contains a regulatory cystathionine β-synthase (CBS) domain, which mediates allosteric modulation by ATP and GTP. However, MsmGMPR exhibits an atypical tertiary structure that is incompatible with the acknowledged regulatory mechanisms of IMPDH/GMPR family enzymes. Here, we combine X-ray crystallography, cryogenic electron microscopy, and biochemical binding assays to elucidate the molecular basis of MsmGMPR regulation by ATP and GTP. We show that ATP stabilises a compressed conformation that inhibits the enzyme by restricting access to the active site and preventing NADPH binding. In contrast, GTP counteracts ATP binding, promoting an active conformation that enables catalysis. Our results provide insight into how MsmGMPR senses and responds to the purine nucleotide balance, revealing a distinct utilisation of the CBS domain compared with its typical role in IMPDH/GMPR enzymes.

PubMed: 41974687
DOI: 10.1038/s41467-026-71657-9

Experimental method

X-RAY DIFFRACTION (2.3 Å)