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<p>Inositol polyphosphate 5-phosphatase K (INPP5K) is a phosphatidylinositol (3,4,5)-trisphosphate phosphatase that increases glucose uptake and regulates myogenesis in the skeletal muscle. To understand the mechanism of its species-specific inhibition, we determined the 1.9-Å resolution crystal structure of human INPP5K in complex with a selective inhibitor, CPD-1 (IC<sub>50</sub> = 2.9&#xa0;µM). The structure reveals that CPD-1 binds to a novel allosteric pocket, inducing a large conformational change in α-helix 3 that alters the active site and prevents substrate binding. This finding explains its unique, noncompetitive inhibitory mechanism. Crucially, while the inhibitor-binding residues are conserved, the key residue governing the allosteric transition is not conserved in mouse and rat INPP5K, which correlates with their insensitivity to CPD-1 (IC<sub>50</sub> &gt; 100&#xa0;µM). Based on these structural insights, we identified the hamster as a pharmacologically relevant preclinical model (IC<sub>50</sub> = 8.2&#xa0;µM). These findings provide a structural basis for the rational design of next-generation INPP5K inhibitors and establish a suitable animal model for their evaluation.</p>

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Crystal structure of human INPP5K with an allosteric inhibitor reveals the structural basis for species specific potency

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月26日

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  • Akihiro Nomura,
  • Keishi Yamaguchi,
  • Motoaki Kawano,
  • Kazuki Hanada,
  • Jun Nishihata,
  • Masato Noguchi,
  • Tsuyoshi Adachi

摘要

Inositol polyphosphate 5-phosphatase K (INPP5K) is a phosphatidylinositol (3,4,5)-trisphosphate phosphatase that increases glucose uptake and regulates myogenesis in the skeletal muscle. To understand the mechanism of its species-specific inhibition, we determined the 1.9-Å resolution crystal structure of human INPP5K in complex with a selective inhibitor, CPD-1 (IC50 = 2.9 µM). The structure reveals that CPD-1 binds to a novel allosteric pocket, inducing a large conformational change in α-helix 3 that alters the active site and prevents substrate binding. This finding explains its unique, noncompetitive inhibitory mechanism. Crucially, while the inhibitor-binding residues are conserved, the key residue governing the allosteric transition is not conserved in mouse and rat INPP5K, which correlates with their insensitivity to CPD-1 (IC50 > 100 µM). Based on these structural insights, we identified the hamster as a pharmacologically relevant preclinical model (IC50 = 8.2 µM). These findings provide a structural basis for the rational design of next-generation INPP5K inhibitors and establish a suitable animal model for their evaluation.