tetano
Editor, Senior Moderator
Biophys J
. 2021 Feb 17;S0006-3495(21)00146-6.
doi: 10.1016/j.bpj.2021.01.037. Online ahead of print.
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors
A Sofia F Oliveira[SUP] 1 [/SUP], Amaurys Avila Ibarra[SUP] 2 [/SUP], Isabel Bermudez[SUP] 3 [/SUP], Lorenzo Casalino[SUP] 4 [/SUP], Zied Gaieb[SUP] 4 [/SUP], Deborah K Shoemark[SUP] 5 [/SUP], Timothy Gallagher[SUP] 6 [/SUP], Richard B Sessions[SUP] 7 [/SUP], Rommie E Amaro[SUP] 4 [/SUP], Adrian J Mulholland[SUP] 8 [/SUP]
Affiliations
Abstract
Changeux et al. recently suggested that the SARS-CoV-2 spike protein may interact with nicotinic acetylcholine receptors (nAChRs), and that such interactions may be involved in pathology and infectivity. This hypothesis is based on the fact that the SARS-CoV-2 spike protein contains a sequence motif similar to known nAChR antagonists. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the spike, to investigate the possible binding of the Y674-R685 region of the spike to nAChRs. We examine the binding of the Y674-R685 loop to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγδ receptor from Tetronarce californica. Our results predict that Y674-R685 has affinity for nAChRs. The region of the spike responsible for binding contains a PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. The conformational behaviour of the bound Y674-R685 is highly dependent on the receptor subtype: it adopts extended conformations in the α4β2 and α7 complexes, but is more compact when bound to the muscle-like receptor. In the α4β2 and αβγδ 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 α7 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 simulations of the glycosylated spike show that the Y674-R685 region is accessible for binding. We suggest a potential binding orientation of the spike protein with nAChRs, in which they are in a non-parallel arrangement to one another.
. 2021 Feb 17;S0006-3495(21)00146-6.
doi: 10.1016/j.bpj.2021.01.037. Online ahead of print.
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors
A Sofia F Oliveira[SUP] 1 [/SUP], Amaurys Avila Ibarra[SUP] 2 [/SUP], Isabel Bermudez[SUP] 3 [/SUP], Lorenzo Casalino[SUP] 4 [/SUP], Zied Gaieb[SUP] 4 [/SUP], Deborah K Shoemark[SUP] 5 [/SUP], Timothy Gallagher[SUP] 6 [/SUP], Richard B Sessions[SUP] 7 [/SUP], Rommie E Amaro[SUP] 4 [/SUP], Adrian J Mulholland[SUP] 8 [/SUP]
Affiliations
- PMID: 33609494
- DOI: 10.1016/j.bpj.2021.01.037
Abstract
Changeux et al. recently suggested that the SARS-CoV-2 spike protein may interact with nicotinic acetylcholine receptors (nAChRs), and that such interactions may be involved in pathology and infectivity. This hypothesis is based on the fact that the SARS-CoV-2 spike protein contains a sequence motif similar to known nAChR antagonists. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the spike, to investigate the possible binding of the Y674-R685 region of the spike to nAChRs. We examine the binding of the Y674-R685 loop to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγδ receptor from Tetronarce californica. Our results predict that Y674-R685 has affinity for nAChRs. The region of the spike responsible for binding contains a PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. The conformational behaviour of the bound Y674-R685 is highly dependent on the receptor subtype: it adopts extended conformations in the α4β2 and α7 complexes, but is more compact when bound to the muscle-like receptor. In the α4β2 and αβγδ 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 α7 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 simulations of the glycosylated spike show that the Y674-R685 region is accessible for binding. We suggest a potential binding orientation of the spike protein with nAChRs, in which they are in a non-parallel arrangement to one another.