The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, 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), the Glu-rich acidic domain (also called “hypervariable region”), a macrodomain (also named “X domain”), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2^pro), the Nsp3 ectodomain (3Ecto, also called “zinc-finger domain”), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth.

多结构域非结构蛋白3（Nsp3）是冠状病毒（CoV）基因组编码的最大蛋白，平均分子量约为200 kD。Nsp3是复制/转录复合体的重要组成部分。它包含多个结构域，由于某些结构域的重复或缺失，其结构在CoV属之间有所不同。但是，所有已知CoV中都存在Nsp3的八个域：泛素样域1（Ubl1），富含Glu的酸性域（也称为“高变区”），宏域（也称为“ X域”），泛素样结构域2（Ubl2），木瓜蛋白酶样蛋白酶2（PL2 ^pro），Nsp3胞外域（3Ecto，也称为“锌指域”）以及未知功能的域Y1和CoV-Y。此外，所有CoV中都存在两个跨膜区域TM1和TM2。自2003年严重急性呼吸系统综合症冠状病毒（SARS-CoV）爆发以来，已经通过X射线晶体学和/或核磁共振（NMR）光谱研究了Nsp3 N末端三分之二域的三维结构。以及2012年的中东呼吸系统综合症冠状病毒（MERS-CoV）。在本综述中，将深入讨论Nsp3这些域的结构和功能。