Unexpected fold in the circumsporozoite protein target of malaria vaccines

Circumsporozoite (CS) protein is themajor surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandemrepeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severemalaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a singleunit, 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 epitopesmap 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 andmedicinal chemical investigation of the conserved hydrophobic pocket.