Summary for 9BC4
| Entry DOI | 10.2210/pdb9bc4/pdb |
| Descriptor | Protein-glutamine gamma-glutamyltransferase 2, HB-225 (gluten peptidomimetic TG2 inhibitor), CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | transglutaminase 2, intermediate state, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 78265.79 |
| Authors | Sewa, A.S.,Mathews, I.I.,Khosla, C. (deposition date: 2024-04-07, release date: 2024-07-03, Last modification date: 2024-07-17) |
| Primary citation | Sewa, A.S.,Besser, H.A.,Mathews, I.I.,Khosla, C. Structural and mechanistic analysis of Ca 2+ -dependent regulation of transglutaminase 2 activity using a Ca 2+ -bound intermediate state. Proc.Natl.Acad.Sci.USA, 121:e2407066121-e2407066121, 2024 Cited by PubMed Abstract: Mammalian transglutaminases, a family of Ca-dependent proteins, are implicated in a variety of diseases. For example, celiac disease (CeD) is an autoimmune disorder whose pathogenesis requires transglutaminase 2 (TG2) to deamidate select glutamine residues in diet-derived gluten peptides. Deamidation involves the formation of transient γ-glutamyl thioester intermediates. Recent studies have revealed that in addition to the deamidated gluten peptides themselves, their corresponding thioester intermediates are also pathogenically relevant. A mechanistic understanding of this relevance is hindered by the absence of any structure of Ca-bound TG2. We report the X-ray crystallographic structure of human TG2 bound to an inhibitory gluten peptidomimetic and two Ca ions in sites previously designated as S1 and S3. Together with additional structure-guided experiments, this structure provides a mechanistic explanation for how S1 regulates formation of an inhibitory disulfide bond in TG2, while also establishing that S3 is essential for γ-glutamyl thioester formation. Furthermore, our crystallographic findings and associated analyses have revealed that i) two interacting residues, H305 and E363, play a critical role in resolving the thioester intermediate into an isopeptide bond (transamidation) but not in thioester hydrolysis (deamidation); and ii) residues N333 and K176 stabilize preferred TG2 substrates and inhibitors via hydrogen bonding to nonreactive backbone atoms. Overall, the intermediate-state conformer of TG2 reported here represents a superior model to previously characterized conformers for both transition states of the TG2-catalyzed reaction. PubMed: 38959038DOI: 10.1073/pnas.2407066121 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.84 Å) |
Structure validation
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