SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development

Abstract

The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.

Keywords: antibodies; antiviral compounds; protein structure; severe acute respiratory syndrome coronavirus 2; vaccines.

Figure 1

(A) Schematic of SARS-CoV-2 spike protein primary structure. Different domains are shown by different colors. SS, single sequence; NTD, N-terminal domain; RBD, receptor-binding domain; SD1, subdomain 1; SD2, subdomain 2; S1/S2, S1/S2 protease cleavage site; S2’, S2’ protease cleavage site; FP, fusion peptide; HR1, heptad repeat 1; CH, central helix; CD, connector domain; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail. The protease cleavage site is indicated by arrows. (B) Cryo-EM structure of the SARS-CoV-2 spike protein. The closed state (PDB: 6VXX) of the SARS-CoV-2 S glycoprotein (left) the open state (PDB: 6VYB) of the SARS-CoV-2 S glycoprotein (right).

Figure 2

(A) The overall structure of SARS-CoV-2 RBD bound with ACE2. ACE2 is colored cyan, SARS-CoV-2 RBD core is colored green (PDB: 6M0J). (B) Different interactions between SARS-CoV-2 RBD/ACE2 (PDB: 6M0J) and SARS-CoV RBD/ACE2 (PDB: 2AJF) that contribute to binding affinity difference. ACE2 is colored cyan. The RBD of SARS-CoV-2 is green, and the RBD of SARS-CoV is orange. Hydrogen bond between Q493 and E35 is represented by dash lines. Salt-bridge between ACE2 D30 and SARS-CoV-2 K417 is represented by dash lines.

Figure 3

(A) The structure of nsp12-nsp7-nsp8 complex. Color marks: nsp7, magenta; nsp8-1 and nsp8-2, grey; β-hairpin, cyan; NiRAN, yellow; the interface, orange; the fingers domain, blue; the palm domain, red; the thumb domain, green. (PDB: 6M71) (B) The structure of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) in active form. The nsp12-nsp7-nsp8 complex bound to the template-primer RNA. (PDB: 7BV2).

Figure 4

The crystal structure of the antibody-RBD/spike protein complex. (A) Crystal structure of CR3022 in complex with SARS-CoV-2 RBD. CR3022 heavy chain is colored in cyan and light chain in yellow. The SARS-CoV-2 RBD in colored in magenta (PDB: 6W41). (B) The crystal structure of B38/SARS-CoV-2 RBD. The heavy chain of B38 is colored magenta and the light chain is colored green. The RBD is colored cyan (PDB: 7BZ5). (C) The crystal structure of CB6-Fab/SARS-CoV-2-RBD. The heavy chain of CB6 is colored magenta and the light chain of CB6 is colored cyan. The SARS-CoV-2-RBD is colored green (PDB: 7C01). (D) The crystal structure of P2B-2F6 Fab/SARS-CoV-2 RBD complex. The light chain of P2B-2F6 Fab is colored yellow and the heavy chain is colored cyan. The SARS-CoV-2 RBD is colored magenta (PDB: 7BWJ). (E) The crystal structure of the complex of SARS-CoV-2 spike RBD bound to Fab fragments of REGN10933 and REGN10987. REGN10933 heavy and light chains are cyan and green, and REGN10987 heavy and light chains are magenta and yellow, respectively (PDB: 6XDG). (F) The crystal structure of BD-23 Fab/spike protein trimer complex. The light chain of BD-23 Fab is colored blue and the heavy chain is colored magenta. The three protomers in the spike protein trimer are colored cyan (A), green (B), and yellow (C) (PDB: 7BYR).

Figure 5

The crystal structure of N3 and its inhibitors. (A) The crystal structure of N3-main protease complex. The main protease is colored brightorange. N3 is colored green (PDB: 6LU7). (B) The crystal structure of 11a-main protease complex. The main protease is colored brightorange, 11a is blue (PDB: 6LZE). (C) The crystal structure of 11b-main protease complex. The main protease is brightorange, 11b is red (PDB: 6M0K). (D) The crystal structure of Carmofur-main protease complex. The main protease is brightorange, carmofur is cyan (PDB: 7BUY).