@article {530081, title = {An unexpected fold in the circumsporozoite protein target of malaria vaccines}, journal = {Proc Natl Acad Sci USA}, volume = {109}, year = {2012}, pages = {7817-22}, abstract = {Circumsporozoite\ (CS)\ protein\ is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35\% reduction in severe\ malaria\ in the first year postimmunization. We solved crystal structures showing that region III and TSR\ fold\ into a single unit, an "αTSR" domain. The αTSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but αTSR does not. Interestingly, polymorphic T-cell epitopes map to specialized αTSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit\ vaccines\ and functional and medicinal chemical investigation of the conserved hydrophobic pocket.}, author = {Doud, M.B. and Koksal, A.C. and Mi, L.Z. and Song, G. and Lu, C. and Springer, T.A.} }