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<p>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. <i>Mycobacterium smegmatis</i> GMPR (<i>Msm</i>GMPR) contains a regulatory cystathionine β-synthase (CBS) domain, which mediates allosteric modulation by ATP and GTP. However, <i>Msm</i>GMPR 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&#xa0;electron microscopy, and biochemical binding assays to elucidate the molecular basis of <i>Msm</i>GMPR 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 <i>Msm</i>GMPR 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.</p>

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Structural basis for allosteric regulation of mycobacterial guanosine 5´-monophosphate reductase by ATP and GTP

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • Michal Doležal,
  • Zdeněk Knejzlík,
  • Tomáš Kouba,
  • Anatolij Filimoněnko,
  • Hana Šváchová,
  • Matteo Dedola,
  • Martin Klíma,
  • Iva Pichová

摘要

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.