Protein co-scientist aided simulations of the structural and functional impact of O-GlcNAc Transferase TPR domain deletions and amino acid substitutions associated with X-Linked Intellectual Disability

TPR domain deletions and XLID-associated amino acid substitutions in O-GlcNAc transferase (OGT) induce long-range conformational changes and reduce predicted ligand binding, with mid-to-late TPR deletions causing the largest structural disruptions.

• Why it matters: TPR repeats are known to mediate substrate recognition and protein-protein interactions, but how specific repeats and disease variants reshape OGT structure and function is unclear.
• What they did: An integrated computational pipeline using Speak to a Protein (Boltz-2, rDock), plus AlphaFold3 and HDOCK, modeled five truncation isoforms, thirteen single-TPR deletions, and five XLID-associated substitutions; structural effects were quantified by backbone RMSD and function by docking with UDP-GlcNAc, HCF1, and TET1.
• The result: Individual TPR deletions contribute unequally to stability, domain deletion and substitutions show substrate-specific docking changes with TET1 and HCF1, and substitution-linked binding reductions align with reported enzymatic activity decreases in XLID.

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