N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

Tian, Fang; Tong, Bei; Sun, Liang; Shi, Shuting; Zheng, Bin; Wang, Zibin; Dong, Xiao; Zheng, Peng

doi:10.7554/elife.69091

Cited by 278 publications

(217 citation statements)

References 77 publications

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“…The SARS-CoV-2 variants Alpha (lineage B.1.1.7), Beta (B.1.351) and Gamma (P.1), which were first identified in the United Kingdom, South Africa and Brazil, respectively, carry a common N501Y mutation in addition to the D614G mutation (TAbLe 1). Residue 501 is one of the key sites within the RBD involved in ACE2 binding 2,178,179 , and recent preliminary reports demonstrate that N501Y mutation strengthens RBD interaction with hACE2 (refS 180,181 ) and increases the infectivity and virulence of variants containing the mutation [182][183][184] . Interestingly, data indicate that the N501Y substitution also lends the S protein the ability to utilize mouse and rat ACE2 orthologues 182,185,186 , raising concern for the potential of new rodent reservoirs.…”

Section: S Proteins From Sarbecoviruses In Reservoir Speciesmentioning

confidence: 99%

Mechanisms of SARS-CoV-2 entry into cells

Jackson

Farzan

Chen

et al. 2021

Nat Rev Mol Cell Biol

1,705

1,373

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The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

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Section: S Proteins From Sarbecoviruses In Reservoir Speciesmentioning

confidence: 99%

Mechanisms of SARS-CoV-2 entry into cells

Jackson

Farzan

Chen

et al. 2021

Nat Rev Mol Cell Biol

1,705

1,373

View full text Add to dashboard Cite

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“…K417N and E484K strongly disrupt binding of class 1 and class 2 antibodies, respectively (24). N501Y is in or proximal to the class 3 epitope, but does not strongly affect the binding or neutralization of polyclonal convalescent or vaccine-elicited antibodies (8,23), although it enhances the RBD's affinity for its receptor, angiotensin converting enzyme 2 (ACE2) (11,25,26).…”

Section: 351 Sars-cov-2 Variant Lineage Has Mutations In Multiple Spike Epitopesmentioning

confidence: 99%

A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy

Greaney

Starr

Eguia

et al. 2021

Preprint

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Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.

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“…This ACE-2 interaction drives the transmission efficacy. Since most vaccine strategies are based on different spike-related immunogens (6), the RBD residue changes might pose major challenges in vaccine immune evasion capacity and receptor affinity adaptation (7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants

et al. 2021

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The recent identification and rise to dominance of the P.1 and B.1.351 SARS-CoV-2 variants have brought international concern because they may confer fitness advantages. The same three positions in the receptor-binding domain (RBD) are affected in both variants, but where the 417 substitution differs, the E484K/N501Y have co-evolved by convergent evolution. Here we characterize the functional and immune evasive consequences of the P.1 and B.1.351 RBD mutations. E484K and N501Y result in gain-of-function with two different outcomes: The N501Y confers a ten-fold affinity increase towards ACE-2, but a modest antibody evasion potential of plasma from convalescent or vaccinated individuals, whereas the E484K displays a significant antibody evasion capacity without a major impact on affinity. On the other hand, the two different 417 substitutions severely impair the RBD/ACE-2 affinity, but in the combined P.1 and B.1.351 RBD variants, this effect is partly counterbalanced by the effect of the E484K and N501Y. Our results suggest that the combination of these three mutations is a two-step forward and one step back in terms of viral fitness.

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N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

Cited by 278 publications

References 77 publications

Mechanisms of SARS-CoV-2 entry into cells

Mechanisms of SARS-CoV-2 entry into cells

A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy

Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants

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