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PROSITE documentation PDOC51874

Picornavirales 3C/3C-like protease domain profile


Viruses in the order Picornavirales infect different vertebrate, invertebrate, and plant hosts and are responsible for a variety of human, animal, and plant diseases. Viruses in this order have a single-stranded, positive sense RNA (+ssRNA) genome that generally translates a large precusrsor polyprotein. After translation, the viral precursor polyprotein is proteolytically cleaved to generate mature functional viral proteins. This maturation process is usually mediated by (more than one) proteases, and a 3C (for the family Picornaviridae) or 3C-like (3CL) protease (for other families) plays a central role in the cleavage of the viral precursor polyprotein. In addition to its key role in processing the polyprotein, 3C/3C-like protease is able to cleave a number of host proteins to remodel the cellular environment for virus reproduction [1,2,3,4,5,6]. The Picornavirales 3C/3C-like protease domain forms the peptidase family C3 (picornain family) of clan PA [E1].

The 3C/3CL protease domain adopts a chymotrypsin-like fold with a cysteine nucleophile in place of a commonly found serine. Accordingly, 3C and 3C-like proteases partially tolerate a replacement of the catalytic cysteine by a serine, and vice-versa, suggesting that the cysteine and serine perform an analogous catalytic function. The catalytic triad is made of a histidine, an aspartate/glutamate and the conserved cysteine in this sequential order. The 3C/3CL protease domain folds into two antiparallel β barrels that are linked by a loop with a short α-helix in its middle, and flanked by two other α-helices at the N- and C-termini (see <PDB:3Q3X>). The two barrels are topologically equivalent and are formed by six antiparallel β strands with the first four organized into a Greek key motif. The active-site residues are located in the cleft between the two barrels with the nucleophilic Cys from the C-terminal barrel and the general acid base His-Glu/Asp from the N-terminal barrel [1,2,4].

The profile we developed covers the entire 3C/3C-like protease domain.

Last update:

January 2019 / First entry.


Technical section

PROSITE method (with tools and information) covered by this documentation:

PCV_3C_PRO, PS51874; Picornavirales 3C/3C-like protease domain profile  (MATRIX)


1AuthorsBirtley J.R. Knox S.R. Jaulent A.M. Brick P. Leatherbarrow R.J. Curry S.
TitleCrystal structure of foot-and-mouth disease virus 3C protease. New insights into catalytic mechanism and cleavage specificity.
SourceJ. Biol. Chem. 280:11520-11527(2005).
PubMed ID15654079

2AuthorsLe Gall O. Christian P. Fauquet C.M. King A.M.Q. Knowles N.J. Nakashima N. Stanway G. Gorbalenya A.E.
TitlePicornavirales, a proposed order of positive-sense single-stranded RNA viruses with a pseudo-T = 3 virion architecture.
SourceArch. Virol. 153:715-727(2008).
PubMed ID18293057

3AuthorsLee C.-C. Kuo C.-J. Ko T.-P. Hsu M.-F. Tsui Y.-C. Chang S.-C. Yang S. Chen S.-J. Chen H.-C. Hsu M.-C. Shih S.-R. Liang P.-H. Wang A.H.-J.
TitleStructural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds.
SourceJ. Biol. Chem. 284:7646-7655(2009).
PubMed ID19144641

4AuthorsCostenaro L. Kaczmarska Z. Arnan C. Janowski R. Coutard B. Sola M. Gorbalenya A.E. Norder H. Canard B. Coll M.
TitleStructural basis for antiviral inhibition of the main protease, 3C, from human enterovirus 93.
SourceJ. Virol. 85:10764-10773(2011).
PubMed ID21835784

5AuthorsLu G. Qi J. Chen Z. Xu X. Gao F. Lin D. Qian W. Liu H. Jiang H. Yan J. Gao G.F.
TitleEnterovirus 71 and coxsackievirus A16 3C proteases: binding to rupintrivir and their substrates and anti-hand, foot, and mouth disease virus drug design.
SourceJ. Virol. 85:10319-10331(2011).
PubMed ID21795339

6AuthorsYe S. Xia H. Dong C. Cheng Z. Xia X. Zhang J. Zhou X. Hu Y.
TitleIdentification and characterization of Iflavirus 3C-like protease processing activities.
SourceVirology 428:136-145(2012).
PubMed ID22534091


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