Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence

The Journal of Physical Chemistry Letters
Naveen Vankadari

Abstract

The COVID-19 pandemic is an urgent global health emergency, and the presence of Furin site in the SARS-CoV-2 spike glycoprotein alters virulence and warrants further molecular, structural, and biophysical studies. Here we report the structure of Furin in complex with SARS-CoV-2 spike glycoprotein, demonstrating how Furin binds to the S1/S2 region of spike glycoprotein and eventually cleaves the viral protein using experimental functional studies, molecular dynamics, and docking. The structural studies underline the mechanism and mode of action of Furin, which is a key process in host cell entry and a hallmark of enhanced virulence. Our whole-exome sequencing analysis shows the genetic variants/alleles in Furin were found to alter the binding affinity for viral spike glycoprotein and could vary in infectivity in humans. Unravelling the mechanisms of Furin action, binding dynamics, and the genetic variants opens the growing arena of bona fide antibodies and development of potential therapeutics targeting the blockage of Furin cleavage.

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Citations

Dec 22, 2020·Briefings in Bioinformatics·Vaishali P WamanChristine Orengo
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bwalya A WitikaRoderick B Walker
Feb 9, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Dengke TianWenqiang Cao
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Mar 16, 2021·Frontiers in Physiology·Magaiver Andrade SilvaNiels Olsen Saraiva Câmara
Apr 4, 2021·International Journal of Molecular Sciences·Szu-Wei Huang, Sheng-Fan Wang
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Jun 24, 2021·FEMS Microbiology Reviews·Milankumar PatelHoward E Gendelman
Jun 5, 2021·Biophysical Journal·Jacob M RemingtonJianing Li
Jul 29, 2021·The Journal of Physical Chemistry. B·Aditya K PadhiTimir Tripathi

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Methods Mentioned

BETA
PISA
glycosylation
exome sequencing

Software Mentioned

GTIxp
LARMD
GenomeAD
Cluspro
Coot
Pymol
Maestro
DynOmics

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