Coronaviruses (CoVs) are enveloped positive-strand RNA viruses that infect many species, including humans, other mammals, and birds. After infection, the host may develop respiratory, bowel, liver, and neurological diseases. Coronaviruses are divided into four genera: αcoronavirus, βcoronavirus, γcoronavirus, and Deltacoronavirus. SARS, SARS-CoV-2, BatCoV RaTG13 and Bat-SARS-like coronavirus (BATSL-CoVZXC21 and BAT-SL-CoVZC45) belong to the Sarbecovirus subgenus of βcoronavirus [E1].

The CoV replicase gene encodes two overlapping polyproteins, termed pp1a and pp1ab, which mediate viral replication and transcription. The polypeptides pp1a and pp1ab are processed by the action of a main protease (Nsp5) (see <PDOC51442>) and of one or two papain-like proteases (PLpro) (see <PDOC51124>) found in Nsp3 into non-structural proteins (Nsps) to form the replication/ transcription complex (RTC). Among these, Nsp3 is a glycosylated, multidomain, integral membrane protein. Nsp3 plays many roles in the viral life cycle. It can act as a scaffold protein to interact with itself and to bind other viral Nsps or host proteins. In particular, Nsp3 is essential for RTC formation. Nsp3 comprises various domains of functional and structural importance for virus replication, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1) (see <PDOC51943>), the Glu-rich acidic domain (also called “hypervariable region”), a macrodomain (also named “X domain”) (see <PDOC51154>), the ubiquitin-like domain 2 (Ubl2) (see <PDOC51943>), the papain-like protease 2 (PL2pro) (see <PDOC51124>), the Nsp3 ectodomain (3Ecto, also called “zinc-finger domain”), as well as the domains Y1, Y2 and Y3 of unknown functions. The Y1 domain is conserved in all viruses of the order Nidovirales, while Y2 and Y3 are only conserved in all coronaviruses. The three domains from the Y region (Y1 to Y3) are located at the cytosolic side of the ER. The level of their conservation is close to that for the enzymatic domains of Nsp3 and exceeds nonenzymatic ones. From the consistently high conservation of Y1, Y2, and Y3, it has been hypothesize that Y1 to Y3 may form a single functional unit with a conserved enzymatic function [1,2,3].

The CoV Nsp3 Y3 domain possesses a well-ordered globular α/β fold (see <PDB:7RQG>) [4].

The profile we developed covers the entire CoV Nsp3 Y3 domain.