Unexpected fold in the circumsporozoite protein target of malaria vaccines.
Proc Natl Acad Sci U S A
; 109(20): 7817-22, 2012 May 15.
Article
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| MEDLINE
| ID: mdl-22547819
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
/
Modelos Moleculares
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Proteínas Protozoarias
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Malaria Falciparum
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Pliegue de Proteína
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Vacunas contra la Malaria
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Esporozoítos
Límite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos