Residues in bold represent reverse-charge mutations. ( E) Close-in view of HCMV Pentamer distal region as described in (D) with highlighted sites of interaction between Pentamer and NRP2 a2 domain (site 1).

NRP2 a1 appears to interact loosely with HCMV Pentamer, is not well resolved in the cryo-EM map, and is not modeled in the structure. ( D) Close-in view of HCMV Pentamer distal region showing NRP2 a1a2b1b2 domains, UL128-131A, gL, and the gH N terminus. ( C) Front view of HCMV Pentamer complex (shown in ribbon) bound to NRP2 a2b1b2 domains (shown in surface representation). ( B) Schematic domain organization of human NRP2. ( A) HCMV Pentamer from two different strains (Merlin and VR1814) selectively a interacts with NRP2 and not NRP1, as previously described ( 5). HCMV Pentamer also binds to thrombomodulin (THBD) with nanomolar affinity, but a role for THBD in the entry of HCMV has remained enigmatic ( 5). Neuropilin 2 (NRP2) deficiency has been demonstrated to make endothelial and epithelial cells resistant to HCMV infection, indicating a key role of NRP2 as an HCMV receptor ( 5), but the structural basis for this interaction has remained unknown. HCMV receptor binding is thought to provide the triggering signal for the gB glycoprotein to catalyze membrane fusion between virus and host cells, allowing HCMV to enter cells, replicate, and establish its latency ( 7). HCMV exhibits a broad cellular tropism and uses the Pentamer complex to bind to different receptor proteins and infect diverse cell types including epithelial, endothelial, and myeloid cells ( 3вЂ“ 6). HCMV infection is particularly threatening during pregnancy and represents the viral leading cause of congenital birth defects ( 2). Human cytomegalovirus (HCMV) is a member of the betaherpesvirus family, responsible for severe morbidity and mortality in immunocompromised individuals ( 1).

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