Structural Analysis of a Viral Ovarian Tumor Domain Protease from the Crimean-Congo Hemorrhagic Fever Virus in Complex with Covalently Bonded Ubiquitin

Abstract

Crimean-Congo hemorrhagic fever (CCHF) virus is a tick-borne

Genomic Characterization of Yogue, Kasokero, Issyk-Kul, Keterah, Gossas, and Thiafora Viruses: Nairoviruses Naturally Infecting Bats, Shrews, and Ticks

“…The virus sequences in the data set contained each of the conserved domains (regions 1-4) identified in other bunyaviruses, 13 as well as the ovarian tumor (OTU)-like protease domain near the N-terminus (Supplemental Figure 4) that, although detected in various other RNA viruses, is unique to the nairovirus among the Bunyaviridae. 11,42 In CCHFV, this OTU-like cysteine protease has been shown to inhibit NF-κB-dependent host innate immune pathways by de-conjugating ubiquitin and the interferon-stimulated gene 15 (ISG15) product from cellular target proteins. 43 Like other nairoviruses, the L proteins of the viruses in our data set are significantly larger than those of other bunyaviruses due to an extended N-terminal region containing this domain, an extended C-terminal region and a long extension between conserved regions 2 and 3.…”

Fluorometric CCHFV OTU protease assay with potent inhibitors

“…The tick-borne properties of the nairoviruses, and the large L segment existing in their genome make them different from other members of the Bunyaviridae viruses [1,2]. Crimean-Congo Hemorrhagic Fever (CCHF) constitutes a public health treat due to its high mortality rate in hospitalized patients [1][2][3][4][5][6][7][8][9][10]. It has been first reported in both the Crimea and Congo, since then there have been outbreaks in different parts of the world including Africa, Asia, and Eastern Europe [5,9,[11][12][13][14].…”

“…Crimean-Congo Hemorrhagic Fever (CCHF) constitutes a public health treat due to its high mortality rate in hospitalized patients [1][2][3][4][5][6][7][8][9][10]. It has been first reported in both the Crimea and Congo, since then there have been outbreaks in different parts of the world including Africa, Asia, and Eastern Europe [5,9,[11][12][13][14]. Due to the potential travel of CCHFV-infected ticks with migratory birds, CCHF raises a concern regarding general healthcare in the world [15][16][17].…”

Identification of small molecule binding pocket for inhibition of Crimean–Congo hemorrhagic fever virus OTU protease

“…The inhibition of antiviral activity by CCHFV OTU occurs by the removal of ubiquitin (UB) and interferonstimulated gene products 15 (ISG15), modifications occurring in a broad manner in the infected cells in contrast to target-specific OTU containing mammalian proteases (Frias-Staheli et al, 2007;Malakhova and Zhang, 2008;Akutsu et al, 2011;Capodagli et al, 2011Capodagli et al, , 2013. UB and ISG15 share a conserved C terminus motif 'LRLRGG' that is recognized by CCHFV OTU protease (Akutsu et al, 2011;Capodagli et al, 2011).…”

“…The crystal structures of the CCHFV OTU protease bound with human UB and with ISG15 have been resolved and deposited in the protein data bank (3PRP and 3PHX, respectively) (Capodagli et al, 2011;James et al, 2011). A key similarity between the two structures is the binding of UB and ISG15 towards a similar pocket of amino acid residues.…”