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Published on: June 28, 2013
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
Sarah N Zvornicanin1, Ala M Shaqra1, Qiuyu J Huang1
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Abstract:
With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose a potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from the beluga whale. A comparison with the apo structure of SW1 Mpro, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 Mpro. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors.
Insights
This study reveals the crystal structures of key proteases from delta and gamma coronaviruses, offering insights into inhibitor binding. These findings support the development of broad-spectrum antiviral drugs against diverse coronavirus threats.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- The COVID-19 pandemic highlighted the zoonotic threat of coronaviruses (CoVs).
- Research has primarily focused on alpha- and beta-CoVs due to human infections.
- Delta and gamma-CoVs also pose zoonotic risks, necessitating further investigation.
Purpose of the Study:
- To determine the inhibitor-bound crystal structures of the main protease (Mpro) from delta-CoV (porcine HKU15) and gamma-CoV (beluga whale SW1).
- To analyze structural changes upon inhibitor binding.
- To provide a basis for designing pan-coronavirus inhibitors.
Main Methods:
- X-ray crystallography was used to determine the 3D structures of Mpro from HKU15 and SW1.
- Cocrystallization with covalent inhibitors PF-00835231 (lufotrelvir) and GC376 was performed.
- Comparison with the apo structure of SW1 Mpro elucidated binding mechanisms.
Main Results:
- Inhibitor-bound crystal structures of HKU15 Mpro and SW1 Mpro were successfully determined.
- Specific binding modes and interactions of PF-00835231 and GC376 within the Mpro active sites were revealed.
- Structural rearrangements upon inhibitor binding were identified.
Conclusions:
- The determined structures provide crucial insights into the inhibition of delta- and gamma-CoV Mpro.
- These findings can guide the structure-based design of novel covalent inhibitors.
- The study supports the development of pan-coronavirus inhibitors targeting diverse CoV genera.
