Human cytomegalovirus (HCMV) remains a major cause of morbidity and mortality in immunocompromised individuals and newborns worldwide. Current antiviral therapies mainly target the viral DNA polymerase, but their long-term clinical use is often constrained by toxicity and the emergence of drug-resistant strains. The approval of letermovir, the first antiviral targeting the viral terminase complex, has established viral genome packaging as a highly effective therapeutic strategy. The HCMV terminase complex is essential for viral DNA cleavage and encapsidation and lacks direct human homologs, making it an attractive target for selective antiviral intervention. Accumulating evidence indicates that letermovir may primarily target pUL56, as resistance mutations cluster predominantly within this subunit. This review summarizes current understanding of the interaction between letermovir and the HCMV terminase, focusing on structural organization, inhibitory mechanisms, resistance mutations, and emerging approaches for next-generation inhibitor development, and highlighting key unresolved questions that will guide future structure-based antiviral discovery targeting herpesvirus genome packaging machinery.
Guo-Jun Chen, Yu-Qi Li, Jin-Rui Chen et al.· Frontiers in Microbiology· 0 citations
Dear Editor , The detoxi fi cation of phytotoxic compounds is a prerequisite for plant survival. ATP-binding cassette family C (ABCC) transporters play a pivotal role in the export of toxic compounds into vacuoles, a critical step in detoxi fi cation 1 . Arabidopsis thaliana ABCC2 ( At ABCC2) is responsible for the ef fl ux of glutathione conjugates of pesticides, such as atrazine and metolachlor, into the vacuoles 2 – 5 . Additionally, At ABCC2 can export arsenic-phytochelatin conjugates into vacuoles, resulting in increased arsenic tolerance 6,7 . Despite its critical role in plant detoxi fi cation, the biochemical and structural mechanisms underlying the function of At ABCC2 remain incompletely understood. To address this gap, we present cryo-electron microscopy (cryo-EM) structures of At ABCC2 in four states: apo, substrate bound, closed, and dimeric. Structural analysis revealed a unique architecture, distinguished by the atypical localization of its transmembrane domain 0 (TMD0) domain. Moreover, biochemical studies revealed that the TMD0 domain is critical for coordinating transport channel closure. The molecular basis of atrazine export by At ABCC2 was also determined. Additionally, the plant-speci fi c dimerization of At ABCC2 was demonstrated to be mediated by TMD2 and nucleotide-binding domain 2 (NBD2) rather than by the TMD0 domain. Notably, we found that although dimeric At ABCC2 represented a physiological form, its dimerization resulted in reduced substrate export activity. These fi ndings provide new insights into the detoxi fi cation mechanism of At ABCC2 and highlight the potential for using ABCC transporters to develop herbicide-resistant crops. Full-length At
