+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses



Profiling of substrate specificities of 3C-like proteases from group 1, 2a, 2b, and 3 coronaviruses



Plos one 6(11): E27228



Coronaviruses (CoVs) can be classified into alphacoronavirus (group 1), betacoronavirus (group 2), and gammacoronavirus (group 3) based on diversity of the protein sequences. Their 3C-like protease (3CL(pro)), which catalyzes the proteolytic processing of the polyproteins for viral replication, is a potential target for anti-coronaviral infection. Here, we profiled the substrate specificities of 3CL(pro) from human CoV NL63 (group 1), human CoV OC43 (group 2a), severe acute respiratory syndrome coronavirus (SARS-CoV) (group 2b) and infectious bronchitis virus (IBV) (group 3), by measuring their activity against a substrate library of 19 × 8 of variants with single substitutions at P5 to P3' positions. The results were correlated with structural properties like side chain volume, hydrophobicity, and secondary structure propensities of substituting residues. All 3CL(pro) prefer Gln at P1 position, Leu at P2 position, basic residues at P3 position, small hydrophobic residues at P4 position, and small residues at P1' and P2' positions. Despite 3CL(pro) from different groups of CoVs share many similarities in substrate specificities, differences in substrate specificities were observed at P4 positions, with IBV 3CL(pro) prefers P4-Pro and SARS-CoV 3CL(pro) prefers P4-Val. By combining the most favorable residues at P3 to P5 positions, we identified super-active substrate sequences 'VARLQ↓SGF' that can be cleaved efficiently by all 3CL(pro) with relative activity of 1.7 to 3.2, and 'VPRLQ↓SGF' that can be cleaved specifically by IBV 3CL(pro) with relative activity of 4.3. The comprehensive substrate specificities of 3CL(pro) from each of the group 1, 2a, 2b, and 3 CoVs have been profiled in this study, which may provide insights into a rational design of broad-spectrum peptidomimetic inhibitors targeting the proteases.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 055206779

Download citation: RISBibTeXText

PMID: 22073294


Related references

Profiling of substrate-specificity and rational design of broad-spectrum peptidomimetic inhibitors for main proteases of coronaviruses. Hong Kong Medical Journal 20(Suppl. 4): 22-25, 2014

Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities. Journal of Biological Chemistry 281(18): 12824-12832, 2006

Robust substrate profiling method reveals striking differences in specificities of serum and lung fluid proteases. Biotechniques 51(2): 95, 2011

Substrate specificities of caspase family proteases. Journal of Biological Chemistry 272(15): 9677-9682, 1997

Substrate specificities of hemorrhagic proteases from crotalus atrox. Toxicon 23(4): 564, 1985

Conservation of substrate specificities among coronavirus main proteases. Journal of General Virology 83(Pt 3): 595-599, 2002

Studies on new acid proteases from Scytalidium lingnicolumn M-133. IV. Some physicochemical properties and substrate specificities of acid proteases A-1 and A-2 of Scytalidium lignicolumn ATCC 24568. Agricultural and Biological Chemistry 40(5): 859-866, 1976

Substrate specificities of the proteases from a marine psychrophilic bacterium pseudomonas sp no 548. Agricultural & Biological Chemistry 38(1): 103-109, 1974

Substrate Specificities of the Proteases from a Marine-psychrophilic Bacterium, Pseudomonas sp. No. 548. Agricultural and Biological Chemistry 38(1): 103-109, 1974

The CaaX proteases, Afc1p and Rce1p, have overlapping but distinct substrate specificities. Molecular and Cellular Biology 20(12): 4381-4392, 2000

Mycobacterium tuberculosis ClpP proteases are co-transcribed but exhibit different substrate specificities. Plos one 8(4): E60228, 2013

Enzymatic properties, substrate specificities and pH-activity profiles of two kiwifruit proteases. Journal of Nutritional Science and Vitaminology 43(5): 581-589, 1997

Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2. Journal of Biological Chemistry 276(44): 40880-7, 2001

Primary substrate specificities of secreted aspartic proteases of Candida albicans. Advances in Experimental Medicine and Biology 436: 335-338, 1998

Substrate specificities and catalytic mechanisms of serine proteases on the facet of their 3 dimensional structure. Elodi, P (Ed ) Symposia Biologica Hungarica, Vol 25 Proteinase Action; Proceedings Of The International Workshop, Debrecen, Hungary, Aug 29-31, 1983 Ix+475p Akademiai Kiado: Budapest, Hungary Illus 339-354, 1984