Serine 477 plays a crucial role in the interaction of the SARS-CoV-2 spike protein with the human receptor ACE2.

Abstract

Since the worldwide outbreak of the infectious disease COVID-19, several studies have been published to understand the structural mechanism of the novel coronavirus SARS-CoV-2. During the infection process, the SARS-CoV-2 spike (S) protein plays a crucial role in the receptor recognition and cell membrane fusion process by interacting with the human angiotensin-converting enzyme 2 (hACE2) receptor. However, new variants of these spike proteins emerge as the virus passes through the host reservoir. This poses a major challenge for the design of a potent antibody against these spike proteins. Through structural bioinformatics analysis based on normal mode analysis (NMA) we identified a highly flexible region in the receptor binding domain (RBD) of SARS-CoV-2, starting from residue 475 up to residue 485. Structurally, S477 shows the highest rotational degrees of freedom among them. At the same time, S477 is the world’s most frequently mutated residue in the RBD of SARS-CoV-2. Therefore, using advanced MD simulations, we have investigated the role of S477 and its two frequent mutations (S477G and S477N) at the RBD during the binding to hACE2. We found that the amino acid exchanges S477G and S477N strengthen the binding of the SARS-COV-2 spike with the hACE2 receptor.

Phylogenomics and population genomics of SARS-CoV-2 in Mexico during the pre-vaccination stage reveals variants of interest B.1.1.28.4 and B.1.1.222 or B.1.1.519 and the nucleocapsid mutation S194L associated with symptoms

“…Irrespective of the codon usage of SARS-CoV-2 [52], the mutations from E to K (G → A) and from E to Q (G → C) involve single and non-sequential nucleotide point mutations, and thus they may offer alternative solutions to the same phenotype. A similar scenario with multiple combinations at the codon level, within different lineages in Mexico, can be seen in the mutation of concern S477N/I [53]. These mutations appear in seven sequences from different States distributed throughout different lineages (B.1.404 and B.1, for instance), and they involve mutations G → A and G → U in the second letter, respectively, which can be generated from two different sets of codons.…”

“…The first one is in the flexible loop of the RBD, and includes S477N, T478K and E484K. These mutations may affect the interactions between the spike protein and the ACE2 receptor [53, 58]. The other hotspot is within S1–S2 subdomains, and which includes the furin-like protease cleavage site [70, 71], and contains D614G, P681H/R and T732A.…”

“…Mutations T478K and S477N, involving changes from similar hydroxylated side-chains (T and S) into positively charged basic amino acids (K and N), may have analogous functional roles, reinforcing the ability of the virus to bind to the human ACE2 receptor [70]. Interestingly, S477 has been identified as the most flexible amino acid within the RBM and with the largest number of mutations [53], which might be stabilized by mutation T478K. A case exemplifying a similar scenario in which physically close mutations contribute towards an analogous structural solution is provided by the spike protein mutation Q613H.…”

A comprehensive overview of identified mutations in SARS CoV-2 spike glycoprotein among Iranian patients

“…Mutations in Receptor binding motif (RBM): 437–508aa has been showed with stars. Sr. No Mutations Events Possible functional implications 1 R408K 1 Attenuates monoclonal and serum antibody neutralization ( Liu, et al, 2020 ) 2 K417N/T 2 Increases binding of the spike RBD to the ACE2 and higher infectivity ( Khan, 2021 ) 3 N439K* 3 Enhances binding affinity for human ACE2 and confers resistance to numerous neutralizing monoclonal antibodies and permits immune escape from some polyclonal sera ( Flemming, 2021 ) 4 L452R* 9 Evades cellular immunity and increases infectivity ( Motozono, 2021 , Li, 2020 ) 5 S459Y* 1 Might increase binding of the spike RBD to the ACE2 ( Wang, 2021 ) 6 N460I* 1 Could escape some monoclonal antibody ( Starr, 2021 ) 7 S477N* 4 Fortifies the binding of the SARS-COV-2 spike with the hACE2 receptor ( Singh, 2021 ) 8 T478K* 9 Increases the binding of the spike RBD to the ACE2 and escape immune recognition ( Di Giacomo, 2021 , Wang, 2021 ) 9 E484K* 2 Reduces the binding of serum polyclonal neutralizing antibodies ( Jangra, 2021 , Harvey, 2021 ) 10 G485S* 1 Decreases the ability of the S protein to bind ACE2 ( Zhang, et al, 2021 ) 11 N501Y* 9 Enhanced binding of SARS-CoV-2 spike protein to the human ACE2 receptor ( Luan et al, 2021 ) 12 H519Y 1 Replacement of histidine with...…”

Evolutionary trajectory of SARS-CoV-2 and emerging variants

“…A701V, shared by variant B.1.351 [100], is in the S2 subunit adjacent to the furin cleavage site [219] and may impact SARS-CoV-2 cleavability and infectivity. S477N, also found in variant 20A.EU2, increases binding to hACE2 [221,222] and reduces antibody-mediated neutralization [178,223], likely due to its position within a neutralizing epitope [224]. D614G and E484K are shared with multiple other variants (Table 5 [183,225].…”