9Q69

Cryo-electron microscopy structure of PfRIPR bound to monoclonal antibodies RP.047, RP.057 and RP.035

Summary for 9Q69

• Entry DOI: 10.2210/pdb9q69/pdb
• EMDB information: 72260
• Descriptor: RP.047 Heavy Chain, RP.047 Light Chain, RP.057 Heavy Chain, ... (7 entities in total)
• Functional Keywords: malaria, ripr, monoclonal antibodies, vaccine, invasion complex, plasmodium falciparum, immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 7
• Total formula weight: 198501.72

Authors

Barrett, J.R.,Ward, A.B. (deposition date: 2025-08-21, release date: 2026-06-24)

Primary citation

Williams, B.G.,Barrett, J.R.,Scott, J.B.,Rigby, C.A.,Cagiada, M.,Quinkert, D.,McHugh, K.,Huhn, A.,Burnap, S.A.,Gourjault, C.,Byrne, F.,Raghavan, S.S.R.,Rodrigues, A.,Bergamaschi, L.,Balzarotti, B.,Watson, S.,Miller, N.,King, L.D.W.,Donnellan, F.R.,Gladstone, C.A.,Paterson, J.,Scalabrino, S.,Silk, S.E.,Salkeld, J.,Minassian, A.M.,Skinner, K.,Struwe, W.B.,Deane, C.M.,Reece, S.T.,Ward, A.B.,Draper, S.J.
Analysis of monoclonal antibodies against the malaria invasion complex protein RIPR reveals the structural basis for synergistic antibody protection.
Immunity, 2026

PubMed Abstract: Plasmodium falciparum RH5-interacting protein (RIPR) is central to the essential PTRAMP-CSS-RIPR-CyRPA-RH5 (PCRCR) complex, a leading target of blood-stage malaria vaccines. However, mechanisms whereby anti-RIPR antibodies inhibit parasite invasion are poorly understood. We characterized 83 human IgG monoclonal antibodies (mAbs) from RIPR-vaccinated Kymouse platform mice. Single mAbs had minimal neutralizing activity; however, high-level synergistic inhibition was observed with pools of mAbs targeting the RIPR-tail region. Structural characterization and molecular dynamics simulations of RIPR-tail showed that mAbs targeting epidermal growth factor (EGF)-like domains 6-8 (RIPR), but not RIPR or the C-terminal domain (RIPR), synergized to constrain the RIPR-tail conformation. The same antibodies dissociated PTRAMP-CSS from RIPR, thereby enabling anti-RIPR mAbs or anti-CSS single-domain Abs to bind and potentiate anti-RIPR IgG. Addition of these mAbs to IgG from humans immunized with the R78C (RIPR-CyRPA) candidate vaccine enhanced malaria growth inhibition. These data provide a framework to guide next-generation blood-stage malaria vaccine design.

PubMed: 42285102
DOI: 10.1016/j.immuni.2026.05.012

Experimental method

ELECTRON MICROSCOPY (3.35 Å)