Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

“…Another mAb, (R218) binding to residues 304 KNNINN 309 f a r a w a y f r o m c H A B P s 1 7 7 9 ( 500 NIDRIYDKNLLMIKEHILAI 519 ) and 1783 ( 580 HRNKKNDKLYRDEWWKVIKK 599 ) does not inhibit RBC invasion (Figure 2A) (Chen, E. et al, 2013 (Wright et al, 2014) variable aa sequences close t o b u t n o t i n v o l v i n g c H A B P s 3 6 7 3 5 ( 361 DEYIHKLILSVKSKNLNKDL 380 ) and 36739 ( 441 KIKLNIW RTFQKDELLKRIL 460 ) ( Figure 2B). …”

“…(B1) Pf Rh5 (PDB code 4WAT) (Chen, L. et al, 2014) shows cHABPs 36735 (in dark yellow), 36736 (in blue) and 36739 (in purple) that bind to basigin. The crystal structure of Pf Rh5 bound to growthinhibitory monoclonal antibody fragments 9AD4 (PDB code 4U0R) is also shown (Wright et al, 2014). (C1) Pf AMA-1 recombinant fragment (PDB accession number 1Z40) (Bai et al, 2005) containing domains I (residues 108-308) and II (residues 309-436) and the location of RBCbinding cHABPs 4313 (blue) and 4325 (dark yellow), displaying the trough where a still undetermined RBC receptor binds.…”

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“…There has been no demonstration of Rh5 allele-specific immunity [28], additionally Rh5 antibodies were shown to inhibit RBC invasion [29][30][31] and have been associated with protection against malaria [32]. The crystal structures for both EBA175-RII (PDB code 1ZRL) [33] and Rh5 (PDB code 4U0Q) [34] have been published and the residues involved in binding to their respective RBC receptors identified. This therefore makes these two proteins, ideal candidates for the in silico discovery of vaccine targets.…”

“…The crystal structure of EBA175-RII showing (A) the overlap between the predicted CD8+ epitope (aa 553-561) and the glycan binding sites at residues Lys-553 and Met-554, (B) the overlap between the predicted CD4+ epitope (aa 440-456) and the glycan binding sites at residue Asp-442, (C) the overlap between the predicted BCE (aa [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and the glycan binding sites at residues Lys-28, Asn-29, Arg-31, Ser-32 and Asn-33, (D) the overlap between the predicted BCE (aa 420-440) and the glycan binding sites at residue Lys-439 and (E) the overlap between the predicted BCE (aa 528-547) and the glycan binding sites at residues Gln-542 and Tyr-546.…”

Towards an anti-disease malaria vaccine

“…One option, which leads to sterile protection in immunized volunteers, but has challenges associated with deployment in malaria endemic regions, is whole parasite-based vaccines, such as attenuated sporozoites [6]. In addition, promising molecular targets for intervention have been identified for each stage, including components of the circumsporozoite protein (CSP) for the liver stage (already the active component of the RTS,S vaccine) [2], RH5 for the blood stage [7,8] and HAP2, Pfs48/45 and Pfs230 for gamete fusion [9]. All are under active consideration as vaccine candidates.…”