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Consistent with its vital contribution to glucose homeostasis, inactivating mutations in G6PC1 causes glycogen storage disease (GSD) type 1a characterized by hepatomegaly and severe hypoglycemia. Despite its physiological importance, the structural basis of G6P binding to G6PC1 and the molecular disruptions induced by missense mutations within the active site that give rise to GSD type 1a are unknown. In this study, we determine the atomic interactions governing G6P binding as well as explore the perturbations imposed by disease-linked missense variants by subjecting an AlphaFold2 G6PC1 structural model to molecular dynamics simulations and in silico predictions of thermodynamic stability validated with robust in vitro and in situ biochemical assays. We identify a collection of side chains, including conserved residues from the signature phosphatidic acid phosphatase motif, that contribute to a hydrogen bonding and van der Waals network stabilizing G6P in the active site. The introduction of GSD type 1a mutations modified the thermodynamic landscape, altered side chain packing and substrate-binding interactions, and induced trapping of catalytic intermediates. Our results, which corroborate the high quality of the AF2 model as a guide for experimental design and to interpret outcomes, not only confirm the active-site structural organization but also identify previously unobserved mechanistic contributions of catalytic and noncatalytic side chains.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgae036","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T08:05:30Z","timestamp":1706515530000},"source":"Crossref","is-referenced-by-count":8,"title":["Integrative analysis of pathogenic variants in glucose-6-phosphatase based on an AlphaFold2 model"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9206-1895","authenticated-orcid":false,"given":"Matt","family":"Sinclair","sequence":"first","affiliation":[{"name":"Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , Urbana, IL 61801 , USA"},{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign , Urbana, IL 61801 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0541-7150","authenticated-orcid":false,"given":"Richard A","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville, TN 37232 , USA"},{"name":"Center for Applied Artificial Intelligence in Protein Dynamics, Vanderbilt University , Nashville, TN 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9641-7577","authenticated-orcid":false,"given":"Jonathan H","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Center for Structural Biology, Vanderbilt University , Nashville, TN 37240 , USA"},{"name":"Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine , St Louis, MO 63110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3266-3824","authenticated-orcid":false,"given":"Emily M","family":"Hawes","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2153-9761","authenticated-orcid":false,"given":"Richard M","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville, TN 37232 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8434-1010","authenticated-orcid":false,"given":"Emad","family":"Tajkhorshid","sequence":"additional","affiliation":[{"name":"Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , Urbana, IL 61801 , USA"},{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign , Urbana, IL 61801 , USA"},{"name":"Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign , Urbana, IL 61801 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1374-7176","authenticated-orcid":false,"given":"Derek P","family":"Claxton","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville, TN 37232 , USA"},{"name":"Center for Applied Artificial Intelligence in Protein Dynamics, Vanderbilt University , Nashville, TN 37240 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville, TN 37240 , 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