Structural basis of receptor recognition by SARS-CoV-2.

Published on Mar 30, 2020in Nature42.778
· DOI :10.1038/S41586-020-2179-Y
Jian Shang13
Estimated H-index: 13
(UMN: University of Minnesota),
Gang Ye10
Estimated H-index: 10
(UMN: University of Minnesota)
+ 6 AuthorsFang Li41
Estimated H-index: 41
(UMN: University of Minnesota)
Sources
Abstract
A novel SARS-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans1,2. A key to tackling this epidemic is to understand the virus’s receptor recognition mechanism, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor - human ACE2 (hACE2)3,4. Here we determined the crystal structure of the SARS-CoV-2 receptor-binding domain (RBD) (engineered to facilitate crystallization) in complex with hACE2. Compared with the SARS-CoV RBD, a hACE2-binding ridge in SARS-CoV-2 RBD takes a more compact conformation; moreover, several residue changes in SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD/hACE2 interface. These structural features of SARS-CoV-2 RBD enhance its hACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus closely related to SARS-CoV-2, also uses hACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in hACE2 recognition shed light on potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies targeting receptor recognition by SARS-CoV-2.
Download
📖 Papers frequently viewed together
202060.39The Lancet
19 Authors (Fei Zhou, ..., Bin Cao)
12.4k Citations
202060.39The Lancet
14 Authors (Nanshan Chen, ..., Li Zhang)
9,737 Citations
1,384 Citations
References32
Newest
#1Markus Hoffmann (DPZ: German Primate Center)H-Index: 24
#2Hannah Kleine-Weber (DPZ: German Primate Center)H-Index: 11
Last. Stefan Pöhlmann (DPZ: German Primate Center)H-Index: 70
view all 13 authors...
Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SA...
8,074 CitationsSource
#1Alexandra C. Walls (UW: University of Washington)H-Index: 27
#2Young-Jun Park (UW: University of Washington)H-Index: 53
Last. David Veesler (UW: University of Washington)H-Index: 47
view all 6 authors...
Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the...
3,893 CitationsSource
#1Jun Lan (THU: Tsinghua University)H-Index: 7
#1Jun Lan (Ministry of Education)H-Index: 5
Last. Xinquan Wang (Ministry of Education)H-Index: 1
view all 11 authors...
A novel and highly pathogenic coronavirus (SARS-CoV-2) has caused an outbreak in Wuhan city, Hubei province of China since December 2019, and soon spread nationwide and spilled over to other countries around the world1–3. To better understand the initial step of infection at an atomic level, we determined the crystal structure of the SARS-CoV-2 spike receptor-binding domain (RBD) bound to the cell receptor ACE2 at 2.45 A resolution. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly i...
2,105 CitationsSource
#1Tommy Tsan-Yuk Lam (HKU: University of Hong Kong)H-Index: 41
#2Na JiaH-Index: 13
Last. Wu-Chun CaoH-Index: 57
view all 29 authors...
The ongoing outbreak of viral pneumonia in China and beyond is associated with a novel coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are likely reservoir hosts for SARS-CoV-2, the identity of any intermediate host that might have facilitated transfer to humans is unknown. Here, we report the identification of SARS-CoV-2-related coronaviruses in M...
865 CitationsSource
#1Yushun Wan (UMN: University of Minnesota)H-Index: 13
#2Jian Shang (UMN: University of Minnesota)H-Index: 13
Last. Fang Li (UMN: University of Minnesota)H-Index: 41
view all 5 authors...
Recently a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by SARS coronavirus (SARS-CoV). Since SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here we analyzed the potential ...
2,255 CitationsSource
#1Daniel Wrapp (University of Texas at Austin)H-Index: 24
#2Nianshuang Wang (University of Texas at Austin)H-Index: 23
Last. Jason S. McLellan (University of Texas at Austin)H-Index: 59
view all 8 authors...
The outbreak of a novel betacoronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure (MCM) development, we determined a 3.5 A-resolution cryo-EM structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding doma...
4,221 CitationsSource
#1Michael Letko (NIH: National Institutes of Health)H-Index: 13
#2Andrea Marzi (NIH: National Institutes of Health)H-Index: 50
Last. Vincent J. Munster (NIH: National Institutes of Health)H-Index: 77
view all 3 authors...
Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the ...
1,384 CitationsSource
#1Chunyun SunH-Index: 2
#1Liangzhi XieH-Index: 5
Last. Jing LiH-Index: 80
view all 9 authors...
SARS-CoV-2 and SARS-CoV share a common human receptor ACE2. Protein-protein interaction structure modeling indicates that spike-RBD of the two viruses also has similar overall binding conformation and binding free energy to ACE2. In vitro assays using recombinant ACE2 proteins and ACE2 expressing cells confirmed the two coronaviruses9 similar binding affinities to ACE2. The above studies provide experimental supporting evidences and possible explanation for the high transmissibility observed in ...
42 CitationsSource
#1Peng Zhou (CAS: Chinese Academy of Sciences)H-Index: 27
#2Xing-Lou Yang (CAS: Chinese Academy of Sciences)H-Index: 25
Last. Zhengli Shi (CAS: Chinese Academy of Sciences)H-Index: 64
view all 29 authors...
Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome-related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1–4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a novel coronavirus (2019-nCoV) which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started from 12 Dece...
9,599 CitationsSource
#1Qun Li (CCDC: Chinese Center for Disease Control and Prevention)H-Index: 27
#1Li QH-Index: 1
Last. Zijian FengH-Index: 47
view all 45 authors...
Abstract Background The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the...
7,987 CitationsSource
Cited By1614
Newest
#1Maria A. ZoranH-Index: 6
#2Roxana SavastruH-Index: 10
Last. D. TenciuH-Index: 1
view all 6 authors...
While the COVID-19 pandemic is still in progress, being under the fifth COVID-19 wave in Madrid, over more than one year, Spain experienced a four wave pattern. The transmission of SARS-CoV-2 pathogens in Madrid metropolitan region was investigated from an urban context associated with seasonal variability of climate and air pollution drivers. Based on descriptive statistics and regression methods of in-situ and geospatial daily time series data, this study provides a comparative analysis betwee...
Source
#1Kholoud Kahime (Cadi Ayyad University)H-Index: 7
Last. Khalid Elkalay (Cadi Ayyad University)H-Index: 2
view all 0 authors...
Source
#1Sakshi Piplani (Flinders University)H-Index: 3
#2Puneet Kumar SinghH-Index: 16
Last. Nikolai Petrovsky (Flinders University)H-Index: 60
view all 4 authors...
The devastating impact of the COVID-19 pandemic caused by SARS-coronavirus 2 (SARS-CoV-2) has raised important questions about its origins and the mechanism of its transfer to humans. A further question was whether companion or commercial animals could act as SARS-CoV-2 vectors, with early data suggesting susceptibility is species specific. To better understand SARS-CoV-2 species susceptibility, we undertook an in silico structural homology modelling, protein-protein docking, and molecular dynam...
4 CitationsSource
#1Jasmine Cubuk (WashU: Washington University in St. Louis)H-Index: 2
#2Jhullian J Alston (WashU: Washington University in St. Louis)H-Index: 2
Last. Alex S. Holehouse (WashU: Washington University in St. Louis)H-Index: 27
view all 14 authors...
The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA-binding protein critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood. Here we combine single-molecule spectroscopy with all-atom simulations to uncover the molecular details that contribute to N protein function. N protein contains three dynamic disordered regions that house putative transiently-helical binding motifs. The two folded domains interact minimally such that full-leng...
36 CitationsSource
#1Li Guo (Xi'an Jiaotong University)H-Index: 8
#2Zhiqian Yao (Xi'an Jiaotong University)H-Index: 1
Last. Michael G. Kong (ODU: Old Dominion University)H-Index: 18
view all 14 authors...
SARS-CoV-2 is a highly contagious virus and is causing a global pandemic. SARS-CoV-2 infection depends on the recognition of and binding to the cellular receptor human angiotensin-converting enzyme 2 (hACE2) through the receptor-binding domain (RBD) of the spike protein, and disruption of this process can effectively inhibit SARS-CoV-2 invasion. Plasma-activated water efficiently inactivates bacteria and bacteriophages by causing damage to biological macromolecules, but its effect on coronavirus...
11 CitationsSource
#1Mallikarjuna Nimgampalle (IISc: Indian Institute of Science)H-Index: 1
#2Vasudharani Devanathan (IISc: Indian Institute of Science)H-Index: 7
Last. Ambrish Saxena (IITs: Indian Institutes of Technology)H-Index: 2
view all 3 authors...
Recently Chloroquine and its derivative Hydroxychloroquine have garnered enormous interest amongst the clinicians and health authorities' world over as a potential treatment to contain COVID-19 pandemic The present research aims at investigating the therapeutic potential of Chloroquine and its potent derivative Hydroxychloroquine against SARS-CoV-2 viral proteins At the same time screening was performed for some chemically synthesized derivatives of Chloroquine and compared their binding efficac...
13 CitationsSource
#1Dariusz Kowalczyk (Opole University)H-Index: 3
view all 6 authors...
Source
#1Scott BurkholzH-Index: 2
#2Suman Pokhrel (Stanford University)H-Index: 2
Last. Reid M. Rubsamen (Case Western Reserve University)H-Index: 3
view all 11 authors...
Abstract A mutation analysis of SARS-CoV-2 genomes collected around the world sorted by sequence, date, geographic location, and species has revealed a large number of variants from the initial reference sequence in Wuhan. This analysis also reveals that humans infected with SARS-CoV-2 have infected mink populations in the Netherlands, Denmark, United States, and Canada. In these animals, a small set of mutations in the spike protein receptor binding domain (RBD), often occurring in specific com...
1 CitationsSource
#1Martiniano Bello (IPN: Instituto Politécnico Nacional)H-Index: 16
#2Kamrul HasanH-Index: 2
Last. Nazmul HussainH-Index: 1
view all 3 authors...
SARS-CoV-2 is the causative agent of the ongoing viral pandemic of COVID-19. After the emergence of this virus, it became a global public health concern and quickly evolved into a pandemic. Mexico is currently in the third position in the number of deaths due to SARS-CoV-2. To date, there have been several lineages of SARS-CoV-2 worldwide; in the Mexican population, two variants of the spike protein (S-protein) are found, localized at H49Y and D614G, which have been related to increased infectiv...
Source
#1Yen-Pang HsuH-Index: 8
Last. Benjamin F. MannH-Index: 21
view all 5 authors...
Glycans of the SARS-CoV-2 spike protein are speculated to play functional roles in the infection processes as they extensively cover the protein surface and are highly conserved across the variants. To date, the spike protein has become the principal target for vaccine and therapeutic development while the exact effects of its glycosylation remain elusive. Experimental reports have described the heterogeneity of the spike protein glycosylation profile. Subsequent molecular simulation studies pro...
Source