Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, U.S.A.
Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, Brazil.
Biochem Soc Trans. 2023 Aug 31;51(4):1419-1427. doi: 10.1042/BST20200408.
Vaccinia virus is a poxvirus that has been successfully leveraged to develop vaccines for smallpox, which is caused by the closely related Variola virus. Smallpox has been declared as 'eradicated' by the WHO in 1980; however, it still poses a potential bioterrorism threat. More recently, the spreading of monkeypox (MPox) in non-endemic countries has further highlighted the importance of continuing the exploration for druggable targets for poxvirus infections. The vaccinia H1 (VH1) phosphatase is the first reported dual specificity phosphatase (DUSP) able to hydrolyze both phosphotyrosine and phosphoserine/phosphotheonine residues. VH1 is a 20 kDa protein that forms a stable dimer and can dephosphorylate both viral and cellular substrates to regulate the viral replication cycle and host immune response. VH1 dimers adopt a domain swap mechanism with the first 20 amino acids of each monomer involved in dense electrostatic interaction and salt bridge formations while hydrophobic interactions between the N-terminal and C-terminal helices further stabilize the dimer. VH1 appears to be an ideal candidate for discovery of novel anti-poxvirus agents because it is highly conserved within the poxviridae family and is a virulence factor, yet it displays significant divergence in sequence and dimerization mechanism from its human closest ortholog vaccinia H1-related (VHR) phosphatase, encoded by the DUSP3 gene. As the dimeric quaternary structure of VH1 is essential for its phosphatase activity, strategies leading to disruption of the dimer structure might aid in VH1 inhibitor development.
痘苗病毒是一种正痘病毒，已成功用于开发针对由密切相关的天花病毒引起的天花疫苗。1980 年，世界卫生组织宣布天花已被“根除”；然而，它仍然构成潜在的生物恐怖主义威胁。最近，在非流行国家传播的猴痘（MPox）进一步强调了继续探索可用于正痘病毒感染的药物靶点的重要性。痘苗 H1（VH1）磷酸酶是第一个报道的能够水解磷酸酪氨酸和磷酸丝氨酸/磷酸苏氨酸残基的双特异性磷酸酶（DUSP）。VH1 是一种 20 kDa 的蛋白质，形成稳定的二聚体，可使病毒和细胞底物去磷酸化，以调节病毒复制周期和宿主免疫反应。VH1 二聚体采用结构域交换机制，每个单体的前 20 个氨基酸参与密集的静电相互作用和盐桥形成，而 N 端和 C 端螺旋之间的疏水相互作用进一步稳定二聚体。VH1 似乎是发现新型抗痘病毒药物的理想候选物，因为它在痘病毒科中高度保守，是一种毒力因子，但它在序列和二聚化机制上与人类最接近的同源物痘苗 H1 相关（VHR）磷酸酶（由 DUSP3 基因编码）有显著差异。由于 VH1 的二聚体四级结构对于其磷酸酶活性至关重要，因此导致二聚体结构破坏的策略可能有助于 VH1 抑制剂的开发。
