Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

Abstract Placental malaria can have severe consequences for both mother and child effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA glycosaminoglycan chondroitin sulfate A (CS) abundantly present intervillous space. Here, we report cryo-EM structures of ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture a complex domain organization. Notably, surface displays single significantly electropositive patch, compatible with binding negatively charged CS. Using molecular docking dynamics simulations as well comparative hydroxyl radical foot-printing placental CS, identify CS-binding groove, intersecting positively patch central structure. We distinctive conserved structural features upholding macro-molecular CS capacity divergent elements possibly allowing immune escape or near site. These observations will support rational design second-generation vaccines.