Structural Changes at the Zinc Active Site of ACE2 on Binding the SARS-CoV-2 Spike Protein Receptor Binding Domain
Bibliographic record
Abstract
The causative agent of Covid-19 is the SARS-CoV-2 virus. Initiation of cell entry by SARS-CoV-2 is critically dependent upon binding of the SARS-CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2, EC 3.4.17.23). The mechanism of binding of the SARS-CoV-2 spike receptor binding domain to ACE2 is among the most intensively studied infection mechanisms of any pathogen, including a very large number of structural studies. ACE2 is a membrane-associated zinc carboxypeptidase, comprising three domains, the protease domain, a neck domain, and a membrane-spanning α-helical domain. In addition to its role as a carboxypeptidase, ACE2 is also a chaperone for a Na + –amino acid cotransporter called B 0 AT1, and in the presence of B 0 AT1, full-length ACE2 forms dimers. Most studies to date related to Covid-19 have employed just the ACE2 protease domain and have neglected any possible roles of the Zn 2+ -containing ACE2 active site. We show here that ACE2, including the neck domain in addition to the protease domain (and in the absence of B 0 AT1), is dimeric and shows distinctive allostery in its catalytic activity. In contrast, the intensively studied protease domain is monomeric and shows no allostery. Binding of the spike receptor binding domain (RBD) to dimeric ACE2 eliminates its allostery. X-ray absorption spectroscopy of Zn 2+ ACE2 shows distinctive changes in the active site structure upon binding of spike RBD but only in the dimeric form. Taken together, our results indicate that the Zn 2+ -containing active site exhibits a notable level of flexibility and that the dimeric form of ACE2, including both protease and neck domains, likely presents a superior model for the study of ACE2-spike interactions than the monomeric ACE2.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".