4H9K: Crystal structure of cleavage site mutant of Npro of classical swine fever virus

Pestiviruses express their genome as a single polypeptide that is subsequently cleaved into individual proteins by host- and virus-encoded proteases. The pestivirus N-terminal protease (N(pro)) is a cysteine autoprotease that cleaves between its own C-terminus and the N-terminus of the core protein. Due to its unique sequence and catalytic site, it forms its own cysteine protease family C53. After self-cleavage, N(pro) is no longer active as a protease. The released N(pro) suppresses the induction of the host's type-I interferon-alpha/beta (IFN-alpha/beta) response. N(pro) binds interferon regulatory factor-3 (IRF3), the key transcriptional activator of IFN-alpha/beta genes, and promotes degradation of IRF3 by the proteasome, thus preventing induction of the IFN-alpha/beta response to pestivirus infection. Here we report the crystal structures of pestivirus N(pro). N(pro) is structurally distinct from other known cysteine proteases and has a novel "clam shell" fold consisting of a protease domain and a zinc-binding domain. The unique fold of N(pro) allows auto-catalysis at its C-terminus and subsequently conceals the cleavage site in the active site of the protease. Although many viruses interfere with type I IFN induction by targeting the IRF3 pathway, little information is available regarding structure or mechanism of action of viral proteins that interact with IRF3. The distribution of amino acids on the surface of N(pro) involved in targeting IRF3 for proteasomal degradation provides insight into the nature of N(pro)'s interaction with IRF3. The structures thus establish the mechanism of auto-catalysis and subsequent auto-inhibition of trans-activity of N(pro), and its role in subversion of host immune response.
PDB ID: 4H9KDownload
MMDB ID: 114658
PDB Deposition Date: 2012/9/24
Updated in MMDB: 2013/10
Experimental Method:
x-ray diffraction
Resolution: 1.599  Å
Source Organism:
Similar Structures:
Biological Unit for 4H9K: monomeric; determined by author and by software (PISA)
Molecular Components in 4H9K
Label Count Molecule
Protein (1 molecule)
HOG Cholera Virus
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB