Efavirenz Binding Site in HIV-1 Reverse Transcriptase Monomers
Bibliographic record
Abstract
Efavirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of AIDS. NNRTIs bind in a hydrophobic pocket located in the p66 subunit of reverse transcriptase (RT), which is not present in crystal structures of RT without an inhibitor. Recent studies showed that monomeric forms of the p66 and p51 subunits bind efavirenz with micromolar affinity. The effect of efavirenz on the solution conformations of p66 and p51 monomers was studied by hydrogen-deuterium exchange mass spectrometry (HXMS) and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). HXMS data reveal that five peptides, four of which contain efavirenz contact residues seen in the crystal structure of the RT-EFV complex, exhibit a reduced level of exchange in monomer-EFV complexes. Moreover, peptide 232-246 undergoes slow cooperative unfolding-refolding in the bound monomers, but at a rate much slower than that observed in the p66 subunit of the RT heterodimer [Seckler, J. M., Howard, K. J., Barkley, M. D., and Wintrode, P. L. (2009) Biochemistry 48, 7646-7655]. These results suggest that the efavirenz binding site on p66 and p51 monomers is similar to the NNRTI binding pocket in the p66 subunit of RT. Nanoelectrospray ionization FT-ICR mass spectra indicate that the intact monomers each have (at least) two different conformations. In the presence of efavirenz, the mass spectra change significantly and suggest that p51 adopts a single, more compact conformation, whereas p66 undergoes facile, electrospray-induced cleavage. The population shift is consistent with a selected-fit binding mechanism.
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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) | 0.002 | 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".