TY - JOUR
T1 - Unexpected fold in the circumsporozoite protein target of malaria vaccines
AU - Doud, Michael B.
AU - Koksal, Adem C.
AU - Mi, Li Zhi
AU - Song, Gaojie
AU - Lu, Chafen
AU - Springer, Timothy A.
PY - 2012/5/15
Y1 - 2012/5/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84861213666
U2 - 10.1073/pnas.1205737109
DO - 10.1073/pnas.1205737109
M3 - 文章
C2 - 22547819
AN - SCOPUS:84861213666
SN - 0027-8424
VL - 109
SP - 7817
EP - 7822
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -
