PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.
Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation / Monticelli, Maria; Hay Mele, Bruno; Wright, Demi Marie; Guerriero, Simone; Andreotti, Giuseppina; Cubellis, Maria Vittoria. - In: BIOCHIMIE. - ISSN 0300-9084. - (2024). [10.1016/j.biochi.2024.02.011]
Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation
Hay Mele, BrunoSecondo
;Cubellis, Maria VittoriaUltimo
2024
Abstract
PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.File | Dimensione | Formato | |
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