2026-08-06 デラウェア大学（UD）
＜関連情報＞
- https://www.udel.edu/udaily/2026/august/medical-molecular-sciences-superbugs-bacteria-research/
- https://www.sciencedirect.com/science/article/pii/S0969212626001504
GdpPのアロステリック制御に関する構造的知見：立体構造的に動的なホスホジエステラーゼ Structural insights into allosteric regulation of GdpP: A conformationally dynamic phosphodiesterase
Shadikejiang Shataer, Shannon Modla, Leif Boddie, Samiran Subedi, Richard Knappenberger, Mona Batish, Vijay Parashar
Structure Available online: 3 June 2026
DOI:https://doi.org/10.1016/j.str.2026.05.004
Highlights
- Cryo-EM structures of GdpP reveal a tetrameric architecture with asymmetric catalysis
- The degenerate GGDEF domain serves as a scaffolding hub for catalytic domains
- The DHHA1 dimerization interface governs asymmetric catalytic regulation
- A conserved KRSR motif in the GGDEF-DHH linker mediates heme inhibition
Summary
The phosphodiesterase GdpP regulates the bacterial second messenger c-di-AMP and drives antibiotic resistance in Firmicutes, yet the structural basis for its allosteric regulation has remained unknown. Here, we present cryo-EM structures of the cytosolic region of Streptococcus mutans GdpP (SmGdpP74) in apo, heme-CN, and product-bound states, revealing a tetrameric architecture that enables asymmetric catalytic regulation. The non-canonical GGDEF domain functions as a scaffolding hub that positions the DHH-DHHA1 catalytic domains, representing the first example of a GGDEF domain repurposed for heterologous domain stabilization. We identify the DHHA1 dimerization interface as the primary determinant of asymmetric catalysis, and a conserved KRSR motif within the GGDEF-DHH linker as a molecular switch for heme-mediated inhibition. These findings establish a mechanistic framework for GdpP allostery and reveal structural sites for therapeutic targeting of c-di-AMP signaling in pathogenic bacteria.
