7pi2

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PfCyRPA bound to monoclonal antibody Cy.003 Fab fragment

Structural highlights

7pi2 is a 12 chain structure with sequence from Gallus gallus and Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.14Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CYRPA_PLAF7 Essential for the invasion of host erythrocytes by blood stage merozoites (PubMed:22593616, PubMed:25583518, PubMed:27374406, PubMed:28195038, PubMed:28195530). Required for the assembly of the PfRH5 adhesion complex (or invasion complex) composed of CyRPA, RH5 and RIPR at the interface between the merozoite and the host erythrocyte membranes (PubMed:25583518, PubMed:28186186, PubMed:28195038, PubMed:28195530, PubMed:30542156). This facilitates the binding of RH5 to host receptor BSG/basigin, which leads to the establishment of a tight junction between the merozoite and host erythrocyte membranes and allows Ca(2+) release into the erythrocyte (PubMed:27374406, PubMed:28186186, PubMed:30542156).[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Understanding mechanisms of antibody synergy is important for vaccine design and antibody cocktail development. Examples of synergy between antibodies are well-documented, but the mechanisms underlying these relationships often remain poorly understood. The leading blood-stage malaria vaccine candidate, CyRPA, is essential for invasion of Plasmodium falciparum into human erythrocytes. Here we present a panel of anti-CyRPA monoclonal antibodies that strongly inhibit parasite growth in in vitro assays. Structural studies show that growth-inhibitory antibodies bind epitopes on a single face of CyRPA. We also show that pairs of non-competing inhibitory antibodies have strongly synergistic growth-inhibitory activity. These antibodies bind to neighbouring epitopes on CyRPA and form lateral, heterotypic interactions which slow antibody dissociation. We predict that such heterotypic interactions will be a feature of many immune responses. Immunogens which elicit such synergistic antibody mixtures could increase the potency of vaccine-elicited responses to provide robust and long-lived immunity against challenging disease targets.

Heterotypic interactions drive antibody synergy against a malaria vaccine candidate.,Ragotte RJ, Pulido D, Lias AM, Quinkert D, Alanine DGW, Jamwal A, Davies H, Nacer A, Lowe ED, Grime GW, Illingworth JJ, Donat RF, Garman EF, Bowyer PW, Higgins MK, Draper SJ Nat Commun. 2022 Feb 17;13(1):933. doi: 10.1038/s41467-022-28601-4. PMID:35177602[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
4 reviews cite this structure
Current approaches to malaria vaccines.
Duffy et al. (2022)
3 more
15 other articles
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See Also

References

  1. ↑ Dreyer AM, Matile H, Papastogiannidis P, Kamber J, Favuzza P, Voss TS, Wittlin S, Pluschke G. Passive immunoprotection of Plasmodium falciparum-infected mice designates the CyRPA as candidate malaria vaccine antigen. J Immunol. 2012 Jun 15;188(12):6225-37. PMID:22593616 doi:10.4049/jimmunol.1103177
  2. ↑ Reddy KS, Amlabu E, Pandey AK, Mitra P, Chauhan VS, Gaur D. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1179-84. PMID:25583518 doi:10.1073/pnas.1415466112
  3. ↑ Volz JC, Yap A, Sisquella X, Thompson JK, Lim NT, Whitehead LW, Chen L, Lampe M, Tham WH, Wilson D, Nebl T, Marapana D, Triglia T, Wong W, Rogers KL, Cowman AF. Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes. Cell Host Microbe. 2016 Jul 13;20(1):60-71. PMID:27374406 doi:10.1016/j.chom.2016.06.004
  4. ↑ Galaway F, Drought LG, Fala M, Cross N, Kemp AC, Rayner JC, Wright GJ. P113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5. Nat Commun. 2017 Feb 10;8:14333. PMID:28186186 doi:10.1038/ncomms14333
  5. ↑ Favuzza P, Guffart E, Tamborrini M, Scherer B, Dreyer AM, Rufer AC, Erny J, Hoernschemeyer J, Thoma R, Schmid G, Gsell B, Lamelas A, Benz J, Joseph C, Matile H, Pluschke G, Rudolph MG. Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody. Elife. 2017 Feb 14;6. pii: e20383. doi: 10.7554/eLife.20383. PMID:28195038 doi:http://dx.doi.org/10.7554/eLife.20383
  6. ↑ Chen L, Xu Y, Wong W, Thompson JK, Healer J, Goddard-Borger E, Lawrence MC, Cowman AF. Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA. Elife. 2017 Feb 14;6. pii: e21347. doi: 10.7554/eLife.21347. PMID:28195530 doi:http://dx.doi.org/10.7554/eLife.21347
  7. ↑ Wong W, Huang R, Menant S, Hong C, Sandow JJ, Birkinshaw RW, Healer J, Hodder AN, Kanjee U, Tonkin CJ, Heckmann D, Soroka V, Sogaard TMM, Jorgensen T, Duraisingh MT, Czabotar PE, de Jongh WA, Tham WH, Webb AI, Yu Z, Cowman AF. Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion complex. Nature. 2018 Dec 12. pii: 10.1038/s41586-018-0779-6. doi:, 10.1038/s41586-018-0779-6. PMID:30542156 doi:http://dx.doi.org/10.1038/s41586-018-0779-6
  8. ↑ Ragotte RJ, Pulido D, Lias AM, Quinkert D, Alanine DGW, Jamwal A, Davies H, Nacer A, Lowe ED, Grime GW, Illingworth JJ, Donat RF, Garman EF, Bowyer PW, Higgins MK, Draper SJ. Heterotypic interactions drive antibody synergy against a malaria vaccine candidate. Nat Commun. 2022 Feb 17;13(1):933. PMID:35177602 doi:10.1038/s41467-022-28601-4

Contents


PDB ID 7pi2

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