The crystal structure of P. knowlesi DBPalpha DBL domain and its implications for immune evasion

Abstract

Plasmodium vivax invasion of human erythrocytes requires that the ligand domain of the Duffy-binding protein (DBP) recognize its cognate erythrocyte receptor, making DBP a potential target for therapy. The recently determined crystal structure of the orthologous DBP ligand domain of the closely related simian malaria parasite Plasmodium knowlesi provides insight into the molecular basis for receptor recognition and raises important questions about the mechanism of immune evasion employed by the malaria parasite.

Figure 1. Subdomain structure of the P. knowlesi DBPα DBL domain is defined by disulfide bonding

(A) Disulfide bonds, numbered sequentially 1-12, create three subdomains within the DBL ligand domain. (B) The subdomains highlighted by separate colors are connected by flexible linkers and weak hydrophobic forces maintain the subdomain configuration. In this model subdomain 1 is yellow, subdomain 2 is red, subdomain 3 is blue, and residues of the predicted binding pocket for receptor recognition are white.

Figure 2. Three-dimensional structure of the P. knowlesi DBPα DBL

The deduced 3D structure of the DBL ligand domain is depicted as a space-filling model (left side) and the ‘worm’ model (right side) rotated in each representation by 90°. The space filling models show the dimorphic residues as green, polymorphic residues as yellow, residues of the predicted binding pocket for the receptor recognition as white, and residues known to change antigenic character and sensitivity to antibody inhibition in red (K171, W191). Dimorphic and polymorphic residues were determined as those that were dimorphic or polymorphic from Sal I DBP in at least two other strains [16-18, 20-22]. The worm model depicts the amino acid backbone and highlights the alpha helices of the second and third domains. Subdomain 1 is yellow, subdomain 2 is red and subdomain 3 is blue.