Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design
First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis, and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (Mpro), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, Mpro has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 Mpro in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with Mpros from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 Mpro provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.
[…] The structure of HCoV-NL63 Mpro-N3 complex was determined using molecular replacement from that of apo-form HCoV-NL63 Mpro (PDB ID: 3TLO; C. P. Chuck & K. B. Wong, unpublished work). All cross-rotation and translation searches for molecular replacement were performed with Phaser. Cycles of manual adjustment using Coot and subsequent refinement using PHENIX led to a final model with a crystallographic R factor (Rcryst) of 19.4% and a free R factor (Rfree) of 24.1% at 2.85-Å resolution. […]
Human coronavirus NL63, Homo sapiens, SARS coronavirus, Middle East respiratory syndrome-related coronavirus
Bronchiolitis, Infection, Pneumonia
to analyse the site's operation and effectiveness, to display ads tailored to your interests
and to provide you with relevant promotional messages and other information about products,
events and services of ours or our sponsors and partner companies.
These cookies are needed for the site to work and to be optimized.
These cookies are needed to interact with the social network plugins on this site.
These cookies are used to track visitors across websites.
The intention is to display ads that are relevant and engaging for the users.
These cookies are needed in order to better understand how
this site is used and to improve the user experience.
At omicX, we believe trust is of the utmost importance. Transparency allows trust.
This is why we want you to understand what data we collect and how we use it.