Structural and molecular perspectives of SARS-CoV-2

Abstract

Recent emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transpired into pandemic coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been rapidly transmitted across the globe within a short period of time, with more than 106 million cases and 2.3 million deaths. The continuous rise in worldwide cases of COVID-19, transmission dynamics of SARS-CoV-2 including re-infections and enormous case-fatality rates emphasizes the urgent need of potential preventive and therapeutic measures. The development of effective therapeutic and preventive measures relies on understanding the molecular and cellular mechanism of replication exhibited by SARS-CoV-2. The structure of SARS-CoV-2 is ranging from 90-120 nm that comprises surface viral proteins including spike, envelope, membrane which are attached in host lipid bilayer containing the helical nucleocapsid comprising viral RNA. Spike (S) glycoprotein initiates the attachment of SARS-CoV-2 with a widely expressed cellular receptor angiotensin-converting enzyme 2 (ACE2), and subsequent S glycoprotein priming via serine protease TMPRSS2. Prominently, comprehensive analysis of structural insights into the crucial SARS-CoV-2 proteins may lead us to design effective therapeutics molecules. The present article, emphasizes the molecular and structural perspective of SARS-CoV-2 including mechanistic insights in its replication.

Keywords: ACE2; COVID-19; Mpro; Nucleocapsid; SARS-CoV-2; Spike-glycoprotein; nsp10/nsp16 2′-O-methylase.

Fig. 1

Genome and Structure of SARS-CoV-2. The genome size of SARS-CoV-2 encodes for 6–11 open reading frames (ORFs) where six functional ORFs are arranged from 5′ to 3′ as replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M) and nucleocapsid (N) encodes for structural proteins as well as seven putative ORFs interspersed between the structural genes and encodes for accessory proteins. The replicase gene covers 67% of the 5′ genome which encodes for a large polyprotein (pp1ab) that gets proteolytically processed into 16 non-structural proteins (nsps). SARS-CoV-2 has surface structural proteins, namely, spike glycoprotein (S), viral membrane glycoprotein (M) and envelope (E) of which are embedded in host membrane-derived lipid bilayer encapsulating the helical nucleocapsid viral RNA.

Fig. 2

Replication of SARS-CoV-2. SARS-CoV-2 infection initiated upon attachment of Spike glycoprotein with ACE2 receptor followed by receptor mediated internalization. Following entry of SARS-CoV-2, viral RNA releases in and immediately undergoes translation process to generate ORF1a and ORF1b which gets processed to generate into nsps which forms viral replication and transcription complex. During the synthesis of nsps, viral replication organelles comprises of characteristic double-membrane spherules (DMSs) that all together creates a protective microenvironment for genomic viral RNA replication and transcription of subgenomic RNAs. The structural proteins get translocate into the endoplasmic reticulum (ER) membranes and assembled into nucleocapsid and viral envelope at ER-to-Golgi intermediate compartment (ERGIC). SARS-CoV-2 progeny virions released from the infected cell by the process of exocytosis.

Fig. 3

Structures of SARS-CoV-2 proteins. A. Trimeric spike glycoprotein structure showing the closed state of the protein. B. Interaction of RBD and ACE2 is showing the involvement of SARS-CoV-2 receptor binding motif (RBM). C. Structure of main protease (Mpro, also called 3CLpro) has been shown. D. Nucleocapsid protein RNA binding domain has been shown in tetramer form. E. Structure of the nsp10/nsp16 2′-O-methylase showing the nsp16 monomer sitting on top of nsp10 monomer.