Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence

Vankadari, Naveen

doi:10.1021/acs.jpclett.0c01698

Cited by 72 publications

(74 citation statements)

References 39 publications

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“…In coronaviruses, membrane fusion is known to depend on proteolytic cleavage at multiple sites, including the S1/S2 site, located at the interface between the S1 and S2 domains, and the S2’ site located within the S2 domain. These cleavage events can impact infection—in fact, a distinct furin cleavage site present in the SARS-CoV-2 S1/S2 site is not found in SARS-CoV (Vankadari, 2020), and it is thought to increase infectivity through enhanced membrane fusion activity (Walls et al, 2020; Vankadari, 2020; Xia et al, 2020). Consequently, mutations at these sites can alter virulence—for instance, a recent study reported that mutations disrupting the multibasic nature of the S1/S2 site affect SARS-CoV-2 membrane fusion and entry into human lung cells (Hoffmann et al, 2020).…”

Section: Whole-genome Association Analysis Of the Sars-cov-2 Genomesmentioning

confidence: 99%

Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

Hahn

Lee

et al. 2020

Preprint

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SARS-CoV-2 mortality has been extensively studied in relationship to a patient’s predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not understood. To address this issue, we used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome. Specifically, we analyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.

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Section: Whole-genome Association Analysis Of the Sars-cov-2 Genomesmentioning

confidence: 99%

Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

Hahn

Lee

et al. 2020

Preprint

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“…[4][5] This type of cleavage generates two protein fragments, S1 and S2, of which the former exposes a newly created C-terminal polypeptide chain with the sequence RRAR. 6,7 This amino acid motif allows the S1 protein to interact with other cell surface receptors, such as Neuropilins (Nrps). [1][2][3]8 Eventually S1 and S2 separate, with S2 displaying a membrane fusion domain (which was previously largely hidden by S1 in the structure of the virus Spike protein).…”

Section: Main Textmentioning

confidence: 99%

Neuropilin-1 Assists SARS-CoV-2 Infection by Stimulating the Separation of Spike Protein Domains S1 and S2

Buck

2021

Preprint

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The cell surface receptor Neuropilin-1 (Nrp1) was recently identified as a host factor for SARS-CoV-2 entry. As the Spike protein of SARS-CoV-2 is cleaved into the S1 and the S2 domain by furin protease, Nrp1 binds to the newly created C-terminal RRAR amino acid sequence of the S1 domain. In this study, we model the association of a Nrp1 (a2-b1-b2) protein with the Spike protein computationally and analyze the topological constraints in the SARS-CoV-2 Spike protein for binding with Nrp1 and ACE2. Importantly, we study the exit mechanism of S2 from the S1 domain with the assistance of ACE2 as well as Nrp1 by molecular dynamics pulling simulations. In the presence of Nrp1, by binding the S1 more strongly to the host membrane, there is a high probability of S2 being pulled out, rather than S1 being stretched. Thus, Nrp1 binding could stimulate the exit of S2 from the S1 domain, which will likely increase virus infectivity as the liberated S2 domain mediates the fusion of virus and host membranes. Understanding of such a Nrp1-assisted viral infection opens the gate for the generation of protein-protein inhibitors, such as antibodies, which could attenuate the infection mechanism and protect certain cells in a future combination therapy.

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“…Moreover, molecular analyses of furin bound to protein S of SARS-CoV-2, including MD, docking simulations and functional studies, unveiled the mechanisms of furin binding. It also rationalized the genetic variants, giving important indications for antibody and drug research [ 186 ].…”

Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

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SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

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Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence

Cited by 72 publications

References 39 publications

Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

Neuropilin-1 Assists SARS-CoV-2 Infection by Stimulating the Separation of Spike Protein Domains S1 and S2

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

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