8dfh

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Crystal structure of non-neutralizing / interfering human monoclonal antibody 42C3 Fab in complex with MSP1-19Crystal structure of non-neutralizing / interfering human monoclonal antibody 42C3 Fab in complex with MSP1-19

Structural highlights

8dfh is a 3 chain structure with sequence from Homo sapiens 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 2.3Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MSP1_PLAF7 During the asexual blood stage, involved in merozoite egress from host erythrocytes possibly via its interaction with the host cytoskeleton protein spectrin resulting in the destabilization of the host cytoskeleton and thus leading to erythrocyte cell membrane rupture (PubMed:26468747). Involved in the binding to host erythrocytes and is required for host erythrocyte invasion (PubMed:12692305, PubMed:21175202, PubMed:25778531, PubMed:36202833).[1] [2] [3] [4] [5] By binding to host proinflammatory cytokine S100P may interfere with host immune responses.[6] Involved in merozoite invasion of host erythrocytes (PubMed:1694225, PubMed:29511044). May play a role in the biogenesis and/or function of the food vacuole during the intraerythrocytic development (Probable).[7] [8] [9]

Publication Abstract from PubMed

Defining mechanisms of pathogen immune evasion and neutralization are critical to develop potent vaccines and therapies. Merozoite Surface Protein 1 (MSP-1) is a malaria vaccine antigen and antibodies to MSP-1 are associated with protection from disease. However, MSP-1-based vaccines performed poorly in clinical trials in part due to a limited understanding of the protective antibody response to MSP-1 and of immune evasion by antigenic diversion. Antigenic diversion was identified as a mechanism wherein parasite neutralization by a MSP-1-specific rodent antibody was disrupted by MSP-1-specific non-inhibitory blocking/interfering antibodies. Here, we investigated a panel of MSP-1-specific naturally acquired human monoclonal antibodies (hmAbs). Structures of multiple hmAbs with diverse neutralizing potential in complex with MSP-1 revealed the epitope of a potent strain-transcending hmAb. This neutralizing epitope overlaps with the epitopes of high-affinity non-neutralizing hmAbs. Strikingly, the non-neutralizing hmAbs outcompete the neutralizing hmAb enabling parasite survival. These findings demonstrate the structural and mechanistic basis for a generalizable pathogen immune evasion mechanism through neutralizing and interfering human antibodies elicited by antigenic diversion, and provides insights required to develop potent and durable malaria interventions.

Neutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion.,Patel PN, Dickey TH, Hopp CS, Diouf A, Tang WK, Long CA, Miura K, Crompton PD, Tolia NH Nat Commun. 2022 Oct 6;13(1):5888. doi: 10.1038/s41467-022-33336-3. PMID:36202833[10]

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

See Also

References

  1. ↑ Goel VK, Li X, Chen H, Liu SC, Chishti AH, Oh SS. Band 3 is a host receptor binding merozoite surface protein 1 during the Plasmodium falciparum invasion of erythrocytes. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5164-9. PMID:12692305 doi:10.1073/pnas.0834959100
  2. ↑ Ranjan R, Chugh M, Kumar S, Singh S, Kanodia S, Hossain MJ, Korde R, Grover A, Dhawan S, Chauhan VS, Reddy VS, Mohmmed A, Malhotra P. Proteome analysis reveals a large merozoite surface protein-1 associated complex on the Plasmodium falciparum merozoite surface. J Proteome Res. 2011 Feb 4;10(2):680-91. PMID:21175202 doi:10.1021/pr100875y
  3. ↑ Baldwin MR, Li X, Hanada T, Liu SC, Chishti AH. Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells. Blood. 2015 Apr 23;125(17):2704-11. PMID:25778531 doi:10.1182/blood-2014-11-611707
  4. ↑ Das S, Hertrich N, Perrin AJ, Withers-Martinez C, Collins CR, Jones ML, Watermeyer JM, Fobes ET, Martin SR, Saibil HR, Wright GJ, Treeck M, Epp C, Blackman MJ. Processing of Plasmodium falciparum Merozoite Surface Protein MSP1 Activates a Spectrin-Binding Function Enabling Parasite Egress from RBCs. Cell Host Microbe. 2015 Oct 14;18(4):433-44. PMID:26468747 doi:10.1016/j.chom.2015.09.007
  5. ↑ Patel PN, Dickey TH, Hopp CS, Diouf A, Tang WK, Long CA, Miura K, Crompton PD, Tolia NH. Neutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion. Nat Commun. 2022 Oct 6;13(1):5888. doi: 10.1038/s41467-022-33336-3. PMID:36202833 doi:http://dx.doi.org/10.1038/s41467-022-33336-3
  6. ↑ Waisberg M, Cerqueira GC, Yager SB, Francischetti IM, Lu J, Gera N, Srinivasan P, Miura K, Rada B, Lukszo J, Barbian KD, Leto TL, Porcella SF, Narum DL, El-Sayed N, Miller LH, Pierce SK. Plasmodium falciparum merozoite surface protein 1 blocks the proinflammatory protein S100P. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5429-34. PMID:22431641 doi:10.1073/pnas.1202689109
  7. ↑ Blackman MJ, Heidrich HG, Donachie S, McBride JS, Holder AA. A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies. J Exp Med. 1990 Jul 1;172(1):379-82. PMID:1694225 doi:10.1084/jem.172.1.379
  8. ↑ Paul G, Deshmukh A, Kumar Chourasia B, Kalamuddin M, Panda A, Kumar Singh S, Gupta PK, Mohmmed A, Chauhan VS, Theisen M, Malhotra P. Protein-protein interaction studies reveal the Plasmodium falciparum merozoite surface protein-1 region involved in a complex formation that binds to human erythrocytes. Biochem J. 2018 Mar 29;475(6):1197-1209. PMID:29511044 doi:10.1042/BCJ20180017
  9. ↑ Dluzewski AR, Ling IT, Hopkins JM, Grainger M, Margos G, Mitchell GH, Holder AA, Bannister LH. Formation of the food vacuole in Plasmodium falciparum: a potential role for the 19 kDa fragment of merozoite surface protein 1 (MSP1(19)). PLoS One. 2008 Aug 29;3(8):e3085. PMID:18769730 doi:10.1371/journal.pone.0003085
  10. ↑ Patel PN, Dickey TH, Hopp CS, Diouf A, Tang WK, Long CA, Miura K, Crompton PD, Tolia NH. Neutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion. Nat Commun. 2022 Oct 6;13(1):5888. doi: 10.1038/s41467-022-33336-3. PMID:36202833 doi:http://dx.doi.org/10.1038/s41467-022-33336-3

8dfh, resolution 2.30Å

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