Cet article est une Preprint
Les preprints sont des rapports de recherche préliminaires qui n'ont pas été certifiés par l’évaluation par les pairs. Ils ne devraient pas être considérés comme guidant la pratique clinique ou les comportements liés à la santé et ne devraient pas être rapportés dans les médias comme des informations établies.
Les preprints publiées en ligne permettent aux auteurs de recevoir des commentaires rapidement, et toute la communauté scientifique peut évaluer indépendamment le travail et répondre en conséquence. Ces commentaires sont publiés avec les preprints que quiconque peut lire et servir d’évaluation post-publication.
Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors and suggest subtype specificity (preprint)
biorxiv; 2020.
Preprint
Dans Anglais
| bioRxiv | ID: ppzbmed-10.1101.2020.07.16.206680
ABSTRACT
Changeux et al. recently suggested that the SARS-CoV-2 spike (S) protein may interact with nicotinic acetylcholine receptors (nAChRs). Such interactions may be involved in pathology and infectivity. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the S protein, to investigate this nicotinic hypothesis. We examine the binding of the Y674-R685 loop of the S protein to three nAChRs, namely the human 4{beta}2 and 7 subtypes and the muscle-like {beta}{gamma}d receptor from Tetronarce californica. Our results indicate that Y674-R685 has affinity for nAChRs and the region responsible for binding contains the PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. In particular, R682 has a key role in the stabilisation of the complexes as it forms interactions with loops A, B and C in the receptors binding pocket. The conformational behaviour of the bound Y674-R685 region is highly dependent on the receptor subtype, adopting extended conformations in the 4{beta}2 and 7 complexes and more compact ones when bound to the muscle-like receptor. In the 4{beta}2 and {beta}{gamma}d complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation similar to other known nAChR antagonists. In contrast, in the 7 complex, Y674-R685 penetrates deeply into the binding pocket where it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1 and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs.
Texte intégral:
Disponible
Collection:
Preprints
Base de données:
bioRxiv
langue:
Anglais
Année:
2020
Type de document:
Preprint
Documents relatifs à ce sujet
MEDLINE
...
LILACS
LIS