تحلیل ساختار اتصال گیرنده ۲۰۱۹-nCoV
Abstract
1- Introduction
2- Methods
3- Results
4- Discussion
Aknowledgements
References
Abstract
۲۰۱۹-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.
Introduction
A mysterious pneumonia illness was first reported in late December 2019 in Wuhan, China, and has rapidly spread to a dozen of countries including the United States with thousands of infected individuals and hundreds of deaths within a month [1]. Scientists in China have isolated the virus from patients and determined its genetic code. The pathogen responsible for this epidemic is a new coronavirus designated 2019-nCoV by the World Health Organization. 2019-nCoV belongs to the same family of viruses as the well-known severe acute respiratory syndrome coronavirus (SARSCoV) and Middle East respiratory syndrome coronavirus (MERSCoV), which have killed hundreds of people in the past 17 years.
Coronaviruses consist of a large diverse family of viruses. They can be classified into four genera: Alpha-, Beta-, Gamma-, and Delta coronavirus [2,3]. Representative alphacoronaviruses include human coronavirus NL63 (HCoV-NL63), while the betacoronaviruses include the best-known SARS-CoV and MERS-CoV. Based on nucleic acid sequence similarity, the newly identified 2019-nCoV is a betacoronavirus. The entry of all coronaviruses into host cells is mediated by spike glycoprotein that gives coronaviruses a crownlike appearance by forming spikes on their surface. The amino acid sequence of spike glycoprotein consists of a large ectodomain, a single-pass transmembrane anchor, and a short C-terminal intracellular tail [3]. The ectodomain contains a receptor-binding unit S1 and a membrane-fusion unit S2. Electron microscopic imaging illustrated that spike glycoprotein forms a clove-shaped spike with three S1 heads and a trimeric S2 stalk. For a virus to enter a host cell, S1 binds to a specific cell surface receptor via its receptorbinding domain (RBD), and S2 fuses the host cell and viral membranes, enabling the entry of viral genomes into host cells. Specific RBD-receptor binding determines if a cell or animal can be infected and also serves as a target for therapeutic inventions to treat diseases caused by coronaviruses. Previous studies have identified angiotensin converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV [4,5]. In this study, we analyzed the structure of spike glycoprotein RBD of 2019-nCoV and identified a unique feature that potentially allows a high affinity binding to ACE2 in human cells. We further discussed potential candidates for natural hosts of 2019-nCoV, routes of transmission, and strategies to inhibit virus entry for therapeutic applications.