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Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2
Open accessAbstract
The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.
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“Attachment and entry of SARS-CoV-2 to target cells is initiated when the virus engages its cognate receptor, angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the viral Spike protein, also called the S protein37.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [37]
In the citing paper
“The S2 subunit comprises the fusion peptide (FP), double heptad repeat (HR), central helix region (CH), connector domain (CD), transmembrane domain (TMD), and cytoplasmic tail (CT), and the S2 subunit is responsible for mediating the fusion between the virus and the host cell membrane233–236”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [233]
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“To assess the effect of noted RBD mutations on ACE2 binding, the crystal structure of the SARS-CoV-2 spike RBD domain complexed with ACE2 (PDB ID: 6LZG [15]) was used.”
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“This mutation causes a D614G (aspartate to glycine in protein position 614) aa-change of the Spike (S) protein, which is responsible for the initial entry of the virus in the cell via the ACE2 human receptor (Guzzi et al., 2020).”
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Self-citationRapid Generation of Neutralizing Antibody Responses in COVID-19 Patients
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Self-citationReceptor binding and complex structures of human ACE2 to spike RBD from omicron and delta SARS-CoV-2
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“As previously reported (Wang et al., 2020), the binding interface of hACE2 for SARS-CoV-2 RBD is distributed over two patches.”
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“The entry for SARS-CoV-2 involves interactions of S with the ACE2 receptor and known or unidentified attachment cofactors, and subsequent priming of the protein by host cell proteases (Lan et al., 2020; Shang et al., 2020; Wang et al., 2020).”
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“Structurally, RBD consists of two subdomains: a core and an external subdomain (51, 52).”
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Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice
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Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape
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“1016/S2213-2600(20)30320-9; pmid: 33002427 5.”
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SARS-CoV-2, COVID-19 and the aging immune system
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COVID-19 and Cardiovascular Disease
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ACE2, Much More Than Just a Receptor for SARS-COV-2
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SARS‐CoV‐2 nucleocapsid protein phase‐separates with RNA and with human hnRNPs
Perdikari, T. M., Murthy, A. C., Ryan, V. H., Watters, S., Naik, M. T., & Fawzi, N. L. (2020) · The EMBO Journal · doi:10.15252/embj.2020106478 · Cited by 353
“…— the crown-like spike (S) glycoprotein that binds to human ACE2 receptor to mediate the entry of the virus in the host cell (Walls et al , 2020; Wang et al , 2020), the membrane (M) protein that facilitates viral assembly in the endoplasmic reticulum, the ion channel envelope (E) protein,…”
Mycroft‐West, C. J., Su, D., Pagani, I., Rudd, T. R., Elli, S., Gandhi, N. S., Guimond, S. E., Miller, G. J., Meneghetti, M. C. Z., Nader, H. B., et al. (2020) · Thrombosis and Haemostasis · doi:10.1055/s-0040-1721319 · Cited by 368
Zhou, T., Tsybovsky, Y., Gorman, J., Rapp, M., Cerutti, G., Chuang, G., Katsamba, P. S., Sampson, J. M., Schön, A., Bimela, J. S., et al. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.11.004 · Cited by 345
“The exact entry process for SARS-CoV-2 is still being defined but is known to involve spike interaction with the ACE2 receptor (Lan et al., 2020; Shang et al., 2020b; Wang et al., 2020; Zhou et al., 2020a).”
Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19
Ziegler, C. G. K., Miao, V. N., Owings, A. H., Navia, A. W., Tang, Y., Bromley, J. D., Lotfy, P., Sloan, M., Laird, H., Williams, H. B., et al. (2021) · Cell · doi:10.1016/j.cell.2021.07.023 · Cited by 358
“…and viral shedding by asymptomatic or presymp- Cell 184, 1–21, Se This is an open access article und tomatic individuals contributes to enhanced transmissibility (Fears et al., 2020; Meyerowitz et al., 2021) and rapid community spread (Arons et al., 2020; Sakurai et al., 2020; Wang et al., 2020c).”
Structural insights into SARS-CoV-2 proteins
Arya, R., Kumari, S., Pandey, B., Mistry, H., Bihani, S. C., Das, A., Prashar, V., Gupta, G. D., Panicker, L., & Kumar, M. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.11.024 · Cited by 380
“SARS-CoV-2 S protein shares ~77% sequence identity with SARS-CoV S protein, and binds to the human ACE2 receptor for virion’s entry into the host cells.(120,121) The 1273 residues long S protein has two major subunits, S1 and S2 (Fig.”
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An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction
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Khan, A., Zia, T., Suleman, M., Khan, T., Ali, S. S., Abbasi, A. A., Mohammad, A., & Wei, D. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30367 · Cited by 341
“Rapid human‐to‐human transmission is the most striking feature of SARS‐CoV‐2, which enabled its worldwide penetrations (Wang et al., 2020b).”
BackgroundResultInfluentialOudkerk, M., Buller, H. R., Kuijpers, D., van Es, N., Oudkerk, S. F., McLoud, T. C., Gommers, D. A. M. P. J., van Dissel, J., Cate, H. T., & van Beek, E. J. R. (2020) · Radiology · doi:10.1148/radiol.2020201629 · Cited by 345
“SARS-CoV-2 enters cells by endocytosis after binding to the transmembrane angiotensin converting enzyme-2 (ACE2) protein on cells in the lung, heart, blood vessels, kidney, and gastrointestinal tract (2).”
BackgroundMolecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy
Zhang, Q., Xiang, R., Huo, S., Zhou, Y., Jiang, S., Wang, Q., & Yu, F. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00653-w · Cited by 364
Self-citationNeutralization of SARS-CoV-2 by Destruction of the Prefusion Spike
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Erratum To: Syncytia formation by SARS‐CoV‐2‐infected cells
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Skin Aging, Cellular Senescence and Natural Polyphenols
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Towards effective COVID‑19 vaccines: Updates, perspectives and challenges (Review)
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“In the case of SARS-cOV-2, the receptor is the angiotensin converting enzyme 2 (AcE2), which is found in large quantities in the respiratory tract and lung parenchyma (51-54).”
BackgroundWang, Y., Liu, M., & Gao, J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008209117 · Cited by 307
“Curiously, a SARS-CoV neutralizing antibody, 80R, that recognizes the S protein with nanomolar affinity (14) in the same interfacial region of ACE2 does not show detectable binding to the RBD of SARS-CoV-2 (11, 15).”
BackgroundMethodInfluentialACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities
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SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma
Wibmer, C. K., Ayres, F., Hermanus, T., Madzivhandila, M., Kgagudi, P., Oosthuysen, B., Lambson, B. E., de Oliveira, T., Vermeulen, M., van der Berg, K., et al. (2021) · doi:10.1101/2021.01.18.427166
Coinfection with influenza A virus enhances SARS-CoV-2 infectivity
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Self-citationAn aberrant STAT pathway is central to COVID-19
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COVID-19 pandemic: Insights into structure, function, and hACE2 receptor recognition by SARS-CoV-2
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“The equilibrium dissociation constants (KD) for hACE2 interacting with the S proteins have indicated that the binding affinity of SARS-CoV-2-S is several-fold higher than that of SARSCoV [11,17,69].”
BackgroundInfluentialTreatment of Coronavirus Disease 2019 (COVID-19) Patients with Convalescent Plasma
Salazar, E., Perez, K. K., Ashraf, M., Chen, J., Castillo, B., Christensen, P. A., Eubank, T. A., Bernard, D. W., Eagar, T. N., Long, S. W., et al. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.05.014 · Cited by 295
Conde‐Agudelo, A., & Romero, R. J. (2021) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2021.07.009 · Cited by 300
Al-Karmalawy, A. A., Dahab, M. A., Metwaly, A. M., Elhady, S. S., Elkaeed, E. B., Eissa, I. H., & Darwish, K. M. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.661230 · Cited by 294
Tan, T. K., Rijal, P., Rahikainen, R., Keeble, A. H., Schimanski, L. M., Hussain, S., Harvey, R., Hayes, J. W. P., Edwards, J. C., McLean, R. K., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20654-7 · Cited by 287
Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody
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Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?
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“Cell entry and spreading of SARS-CoV-2 has been widely thought to depend on the angiotensinconverting enzyme 2 (ACE2) receptor [57, 58] and the serine protease TMPRSS2 [59].”
BackgroundThree-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2
Youk, J., Kim, T., Evans, K. V., Jeong, Y.-I., Hur, Y., Hong, S. P., Kim, J. H., Yi, K., Kim, S. Y., Na, K. J., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.10.004 · Cited by 266
“Essential features of SARS-CoV-2 virus, including ACE2 dependency for cellular entry, patterns of viral transcription, and structure of the spike protein, have been identified (Hoffmann et al., 2020; Kim et al., 2020a; Walls et al., 2020; Wang et al., 2020).”
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“…et al., 2020; Gordon et al., 2020; Ko et al., 2020; Wang et al., 2020a, 2020b; Wit et al., 2020), tocilizumab, corticosteroids (Loutfy et al., 2003; Smith et al., 2020), certain nucleotide as inhibitors (Elfiky, 2020), COVID-19 protease inhibitors (Liu and Wang, 2020, Table 1) are few to name them.”
SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma
Andreano, E., Piccini, G., Licastro, D., Casalino, L., Johnson, N. V., Paciello, I., Monego, S. D., Pantano, E., Manganaro, N., Manenti, A., et al. (2020) · doi:10.1101/2020.12.28.424451
“The S1 subunit presents two highly immunogenic domains, the N-terminal domain (NTD) and the RBD, which are the major targets of polyclonal and monoclonal neutralizing antibodies (4, 9, 10).”
A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein
Kim, C.-M., Ryu, D.-K., Lee, J., Kim, Y., Seo, J. M., Kim, Y., Jeong, J.-H., Kim, M., Kim, J.-I., Kim, P., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20602-5 · Cited by 283
COVID-19: A review of therapeutic strategies and vaccine candidates
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Engineered ACE2 receptor traps potently neutralize SARS-CoV-2
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“High-resolution ACE2–RBD structures (22, 23) show a large, flat binding interface primarily comprising the N-terminal helices of ACE2 (residues 18 to 90), with secondary interaction sites spanning residues 324 to 361 (Fig.”
BackgroundCOVID-19 outbreak: history, mechanism, transmission, structural studies and therapeutics
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“Specifically, the regions, Leu455 to Pro491 and Asn501 to Val503 show disorder-to-order transitions [61].”
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Neurological manifestations of long-COVID syndrome: a narrative review
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Metadata
- Authors
- Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., Lu, G., Qiao, C., Hu, Y., Yuen, K.-Y., Wang, Q., Zhou, H., Yan, J., & Qi, J.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanxi Agricultural University (CN)
- Anhui University (CN)
- Sichuan University (CN)
- University of Science and Technology of China (CN)
- University of Hong Kong (HK)
- Corresponding author
- Yan, Jinghua
- Qi, Jianxun
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 181
- Issue
- 4
- Pages
- 894-904.e9
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7144619
- OpenAlex
- W3015190630
- Cited by
- 2,892
- References
- 59
- Citations by year
- 2026: 66 · 2025: 151 · 2024: 222 · 2023: 334 · 2022: 565 · 2021: 891 · 2020: 659
- FWCI
- 80.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sichuan Province Science and Technology Support Program (2020YFS0010)
- Zhejiang University (2020XGZX031)
- West China Hospital, Sichuan University (HX-2019-nCoV-004)
- Chinese Academy of Sciences (XDB29010202, 2018119, XDB29040302)
- Sichuan University
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- Southern Medical University
- Ministry of Science and Technology of the People's Republic of China
- National Key Research and Development Program of China (2016YFD0500305)
- National Natural Science Foundation of China (81922044, 81973228, 81621091, 81673358)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- SARS-CoV-2, ACE2, viral entry receptor, spike protein, receptor binding domain, crystal structure, receptor binding affinity, SARS-CoV, antigenic differences, monoclonal antibodies, polyclonal antibodies
- MeSH terms
- Protein Domains, Betacoronavirus, Angiotensin-Converting Enzyme 2, SARS-CoV-2, Amino Acid Sequence, Epitopes, Humans, Peptidyl-Dipeptidase A, Models, Molecular, Phylogeny, Sequence Alignment, Severe acute respiratory syndrome-related coronavirus, Virus Internalization, Spike Glycoprotein, Coronavirus
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