Structural Characterization of SARS-CoV-2: Where We Are, and Where We Need to Be

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread in humans in almost every country, causing the disease COVID-19. Since the start of the COVID-19 pandemic, research efforts have been strongly directed towards obtaining a full understanding of the biology of the viral infection, in order to develop a vaccine and therapeutic approaches. In particular, structural studies have allowed to comprehend the molecular basis underlying the role of many of the SARS-CoV-2 proteins, and to make rapid progress towards treatment and preventive therapeutics. Despite the great advances that have been provided by these studies, many knowledge gaps on the biology and molecular basis of SARS-CoV-2 infection still remain. Filling these gaps will be the key to tackle this pandemic, through development of effective treatments and specific vaccination strategies.

Keywords: COVID19; SARS-CoV-2; coronavirus; cryo-EM; structural biology.

FIGURE 1

Known structures for SARS-CoV-2 proteins. (A) Schematic representation of genomic organization of SARS-CoV-2. Structural proteins are shown in pale blue, non-structural proteins are shown in green and accessory proteins are represented in pale yellow. Where available, a cartoon representation of the 3D structure for each protein is shown. 3D structure representations are based on PDBIDs shown in Table 1, only individual monomers are shown. (B) Schematic representation of an assembled SARS-CoV2 virus. The structural S glycoprotein is depicted through the use of a cartoon representation of its molecular structure (PDBID: 6VXX). E and M proteins are depicted with colored shapes. The nucleocapsid protein binding to viral RNA is represented by a cartoon representation of the molecular structure of its N-terminal domain (PDBID: 6M3M), while the C-terminal domain, whose structure is not available, is depicted with a colored sphere.

FIGURE 2

Different conformations of the SARS-CoV-2 spike protein S. Schematic representation of the stages of SARS-CoV-2 fusion to host cells membrane. The S trimer is exposed on the envelope of assembled viruses in its closed conformation (i). Below the schematic, a cartoon representation of the SARS-CoV-2 protein in its pre-fusion closed conformation (PDBID:6vxx) is shown. Cleavage by furin allows exposure of RBDs in their ‘up’ conformation and binding to ACE2 receptor (ii). The determined molecular structure of the S protein with one RBD open (PDBID:6vyb) is shown below. Following binding to ACE2 and further cleavage from TMPRSS2, additional conformational changes occurs that ultimately lead to the post-fusion conformation of the S protein and cause fusion between viral and host membrane (iii). A cartoon representation of the structure of the post-fusion SARS-CoV-2 trimer is shown below the schematic in part (iii).

FIGURE 3

The SARS-CoV-2 replication-transcription complex. (A) Schematic representation of the non-structural proteins that were reported to intervene during the distinct steps of viral RNA replication. Endoplasmic reticulum rearrangements are performed by the Nsp3-5-6 subcomplex resulting in recruitment of the Nsp proteins, initiating RNA synthesis, proof-reading and capping. (B) Structural representation of the proteins involved in viral RNA replication, as shown in (A). Where protein structures have been determined, cartoon models of the molecular structures are represented, whilst proteins with no structural details are depicted as colored shapes, as in part A. Relative positions and molecular contacts between Nsp proteins represented are based on the experimental evidence reviewed in this manuscript, while putative localization have been provided for those protein whose interaction network is still not determined. PDB IDs for the structures depicted in these figures are reported in Table 1.