{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Larasati YA"],"funding":["Swiss National Science Foundation"],"pagination":["eabn9350"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9544338"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(40)"],"pubmed_abstract":["De novo point mutations in <i>GNAO1</i>, gene encoding the major neuronal G protein Gα<sub>o</sub>, have recently emerged in patients with pediatric encephalopathy having motor, developmental, and epileptic dysfunctions. Half of clinical cases affect codons Gly<sup>203</sup>, Arg<sup>209</sup>, or Glu<sup>246</sup>; we show that these mutations accelerate GTP uptake and inactivate GTP hydrolysis through displacement Gln<sup>205</sup> critical for GTP hydrolysis, resulting in constitutive GTP binding by Gα<sub>o</sub>. However, the mutants fail to adopt the activated conformation and display aberrant interactions with signaling partners. Through high-throughput screening of approved drugs, we identify zinc pyrithione and Zn<sup>2+</sup> as agents restoring active conformation, GTPase activi"],"journal":["Science advances"],"pubmed_title":["Restoration of the GTPase activity and cellular interactions of Gα<sub>o</sub> mutants by Zn<sup>2+</sup> in <i>GNAO1</i> encephalopathy models."],"pmcid":["PMC9544338"],"funding_grant_id":["175658"],"pubmed_authors":["Solis GP","Savitsky M","Koval A","Larasati YA","Valnohova J","Katanaev VL"],"additional_accession":[]},"is_claimable":false,"name":"Restoration of the GTPase activity and cellular interactions of Gα<sub>o</sub> mutants by Zn<sup>2+</sup> in <i>GNAO1</i> encephalopathy models.","description":"De novo point mutations in <i>GNAO1</i>, gene encoding the major neuronal G protein Gα<sub>o</sub>, have recently emerged in patients with pediatric encephalopathy having motor, developmental, and epileptic dysfunctions. Half of clinical cases affect codons Gly<sup>203</sup>, Arg<sup>209</sup>, or Glu<sup>246</sup>; we show that these mutations accelerate GTP uptake and inactivate GTP hydrolysis through displacement Gln<sup>205</sup> critical for GTP hydrolysis, resulting in constitutive GTP binding by Gα<sub>o</sub>. However, the mutants fail to adopt the activated conformation and display aberrant interactions with signaling partners. Through high-throughput screening of approved drugs, we identify zinc pyrithione and Zn<sup>2+</sup> as agents restoring active conformation, GTPase activi","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Oct","modification":"2026-05-28T00:47:34.845Z","creation":"2024-10-17T22:32:52.192Z"},"accession":"S-EPMC9544338","cross_references":{"pubmed":["36206333"],"doi":["10.1126/sciadv.abn9350"]}}