Structure analysis of the receptor binding of 2019-nCoV

Abstract

a b s t r a c t2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.

Renin-angiotensin-aldosterone system and COVID-19 infection

“…Moreover, the affinity of SARS COV2 for ACE2 is greater than that of SARS COV (22,23). This spike protein activation by TMPRSS2 proteases followed by SARS COV2 binding to the extracellular domain of membrane ACE2 explains how the virus binds to and penetrates the cell (see Figure 1 in reference (5)).…”

COVID-19 pathophysiology: A review

“…Human (30). Structural and functional analysis showed that the spike for SARS-CoV-2 also bound to ACE2 (31)(32)(33). ACE2 expression was high in lung, heart, ileum, kidney and bladder (34).…”

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

“…These tentative suggestions were based on the observation that SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor binding domain for its spike protein (Lu et al, 2020;Wan, Shang, Graham, Baric, & Li, 2020), similarly to the coronavirus strain implicated in the 2002-2003 SARS epidemic (Dimitrov, 2003;Ge et al, 2013;Li et al, 2003;Prabakaran et al 2004;Turner, Hiscox, & Hooper, 2004). Moreover, the receptor binding domains of these two coronaviruses share 72% amino acid sequence identity, and molecular simulation has indicated similar ternary structures (Chen, Guo, Pan, & Zhao, 2020). However, SARS-CoV-2 includes a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV, and molecular modeling indicated that the receptor binding domain of SARS-CoV-2 has higher affinity for ACE2 compared with SARS-CoV (Chen et al, 2020).…”

“…Moreover, the receptor binding domains of these two coronaviruses share 72% amino acid sequence identity, and molecular simulation has indicated similar ternary structures (Chen, Guo, Pan, & Zhao, 2020). However, SARS-CoV-2 includes a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV, and molecular modeling indicated that the receptor binding domain of SARS-CoV-2 has higher affinity for ACE2 compared with SARS-CoV (Chen et al, 2020).…”