The Molecular Basis of Human ALKBH3 Mediated RNA <i>N</i><sup><i>1</i></sup>‐methyladenosine (m<sup>1</sup>A) Demethylation
Bibliographic record
Abstract
Abstract N 1 ‐methyladenosine (m 1 A) is a prevalent post‐transcriptional RNA modification, and the distribution and dynamics of the modification play key epitranscriptomic roles in cell development. At present, the human AlkB Fe(II)/α‐ketoglutarate‐dependent dioxygenase family member ALKBH3 is the only known mRNA m 1 A demethylase, but its catalytic mechanism remains unclear. Here, we present the structures of ALKBH3‐oligo crosslinked complexes obtained with the assistance of a synthetic antibody crystallization chaperone. Structural and biochemical results showed that ALKBH3 utilized two β‐hairpins (β4‐loop‐β5 and β′‐loop‐β′′) and the α2 helix to facilitate single‐stranded substrate binding. Moreover, a bubble‐like region around Asp194 and a key residue inside the active pocket (Thr133) enabled specific recognition and demethylation of m 1 A‐ and 3‐methylcytidine (m 3 C)‐modified substrates. Mutation of Thr133 to the corresponding residue in the AlkB Fe(II)/α‐ketoglutarate‐dependent dioxygenase family members FTO or ALKBH5 converted ALKBH3 substrate selectivity from m 1 A to N 6 ‐methyladenosine (m 6 A), as did Asp194 deletion. Our findings provide a molecular basis for understanding the mechanisms of substrate recognition and m 1 A demethylation by ALKBH3. This study is expected to aid structure‐guided design of chemical probes for further functional studies and therapeutic applications.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".