Defining how viruses manipulate lipid phosphoinositides through activation of PI4P kinases to mediate viral replication
Bibliographic record
Abstract
Phosphoinositide kinases are central regulators of myriad cellular processes, and their misregulation is causative of multiple human diseases. We are currently focusing on the structural basis for the regulation of phosphoinositide kinases, specifically the Golgi localised phosphatidylinositol 4‐kinase beta (PI4KB). We have identified a previously uncharacterised protein binding partner of PI4KB, the GTPase regulatory protein c10orf76 , and revealed novel insight into an unexpected PI4K positive feedback loop. Using a combined hydrogen deuterium exchange mass spectrometry (HDX‐MS) and structural biology approach we have defined the molecular basis of regulation by the protein c10orf76, revealing novel insight into the role of these PI4KB in viral replication. This has revealed key insight into unexpected feedback loops with Ras superfamily GTPases. Overall, this approach has provided a novel toolbox of engineered mutations to tease out the molecular basis of regulation of phosphoinositide kinases in both homeostasis and disease, and has revealed novel opportunities for the development of small molecule therapeutics for multiple pathogenic viral infections. Support or Funding Information Research was supported by the Canadian Institute of Health Research (CRN‐142393), and salary award for the CIHR new investigator and MSFHR scholar programs.
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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 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".