Molecular studies of the structure-function relationships of Psuedomonas aeruginosa OprM : an outer membrane protein associated with efflux
Bibliographic record
Abstract
Pseudomonas aeruginosa demonstrates high intrinsic resistance to multiple classes of structurally unrelated antimicrobial agents. This broad-spectrum resistance is primarily due to a combination of low outer membrane permeability coupled to secondary resistance mechanisms such as the resistance-nodulation-division (RND) efflux systems. The outer membrane protein OprM is involved in intrinsic and mutational multiple-antibiotic resistance as part of two RND efflux systems in P. aeruginosa. To study structure-function relationships for OprM, optimal conditions for oprM overexpression were determined; it appeared that excessive production of the protein was lethal to cells. In addition, overexpression of oprM alone in wild-type P. aeruginosa did not increase the resistance of the cells, suggesting OprM could not function independent of the pump and linker proteins of the efflux systems. OprM was demonstrated for the first time to have channel-forming activities like porins, and was shown to be cation selective like the related TolC protein of Escherichia coli. Based on the functional and sequence similarity between OprM and TolC, and their similar content of a-helical and P-sheet structures determined by circular dichroism spectroscopy, a three-dimensional model of OprM was constructed by threading its sequence to the TolC crystal structure. This suggested that, like TolC, OprM has a distinctive architecture comprising outer membrane p-barrel and periplasmic helical-barrel structures. Analyses of OprM insertion and deletion mutants in the context of this model indicated that the helical barrel is critical for both function and integrity of OprM, while a C-terminal domain localized around the equatorial plane of this helical barrel is dispensable. Unlike the classic porins, extracellular loops appear to play a minimal role in substrate specificity. There appears to be a correlation between the change in antimicrobial activity for certain OprM mutants and the channel size determined by planar bilayer analysis, supporting the "iris" mechanism of action first suggested for TolC. This study provids information on the structure-function relationships of OprM in a three-dimensional context, and will allow more focused hypotheses and studies about the functional domains of OprM and its related family of efflux proteins.
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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) | 0.000 | 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".