9PUV
Insulin receptor bound to S961
Summary for 9PUV
| Entry DOI | 10.2210/pdb9puv/pdb |
| EMDB information | 71877 |
| Descriptor | Isoform Long of Insulin receptor, S961 Insulin receptor antagonist (2 entities in total) |
| Functional Keywords | antagonist, receptor tyrosine kinase, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 321775.09 |
| Authors | Vogel, A.,Blakely, A.,Hill, C.P. (deposition date: 2025-07-31, release date: 2026-06-10, Last modification date: 2026-06-17) |
| Primary citation | Vogel, A.,Blakely, A.,Dao, Y.,Lin, N.-P.,Chou, D.,Hill, C.P. Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2 Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Oxidative stress induces damage to DNA, RNA, and nucleotide pools. Unlike well-studied DNA damage, the formation of RNA damage and the impact of an oxidized ribonucleotide pool on transcription fidelity are poorly understood. Here, we investigate the structural basis of transcription-coupled RNA damage and the effect of 8-oxo-guanosine triphosphate (8-oxo-rGTP) on RNA polymerase II (Pol II) transcription fidelity control steps. We revealed that the incorporation efficiency of 8-oxo-rGTP opposite a dC template is comparable to that of GTP. In contrast, the incorporation efficiency of 8-oxo-rGTP opposite a dA template is ~150-fold more efficient than that of GTP. For the extension step, Pol II extends substantially faster from a 3'-8-oxo-rG:dC base pair than from a 3'-8-oxo-rG:dA base pair. For the proofreading step, strikingly, Pol II EC with 3'-8-oxo-rG:dA base pair is much more resistant to backtracking and proofreading than Pol II EC with 3'-8-oxo-rG:dC base pair. Using X-ray crystallography, we revealed that 8-oxo-rGTP adopts different prechemistry binding sites depending on whether it is paired with a dC or a dA template. Upon incorporation, the nucleobase of 8-oxo-rG flips to the -conformation to form a Hoogsteen pair with a dA template, whereas it remains in the -conformation to form a Watson-Crick pair with a dC template. Collectively, our work demonstrates that nucleotide-pool oxidation can directly affect Pol II fidelity control steps and elongation dynamics and induce RNA damage in a transcription-coupled manner. PubMed: 41980106DOI: s41467-026-73851-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.68 Å) |
Structure validation
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