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PreprintCited by 0Malaria Research and ControlBiochemical and Structural CharacterizationEnzyme Structure and Function

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Crystal structure and nanobodies against domain 3 of the malaria parasite fusogen Plasmodium falciparum HAP2

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Lyons, Frankie M. T., Chmielewski, Jill, Chan, Li-Jin, Gabriela, Mikha, Chan, Rainbow W. B., Adair, Amy, Tong, Joshua, Pymm, Phillip, Zeglinski, Kathleen, Gouil, Quentin, Tham, Wai-Hong, Dietrich, Melanie H.·2025·Biochemical Journal
DOI 10.64898/2025.12.01.691709PMC PMC12905498

Preprint — published as 10.1042/bcj20250297

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Abstract

Malaria parasites are transmitted to humans through a bite from an infected female Anopheles mosquito. Within the mosquito midgut, malaria parasite gametes are activated and undergo fertilisation. If parasite fertilisation is perturbed, this stops the transmission of malaria parasites from mosquito to human. One proposed target of transmission-blocking interventions is Plasmodium falciparum fusogen PfHAP2, which is essential for gamete fusion during parasite fertilisation. However, to date, no monoclonal antibodies or structures of PfHAP2 have been generated. We have identified nanobodies that bind specifically to domain 3 of PfHAP2 with nanomolar affinities, two of which show some cross-species reactivity with HAP2 of other Plasmodium species. The crystal structure of one nanobody in complex with domain 3 of PfHAP2 provides the first structural insights into this transmission-blocking target in P. falciparum .

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Metadata

Authors
Lyons, F. M. T., Chmielewski, J., Chan, L.-J., Gabriela, M., Chan, R. W. B., Adair, A., Tong, J., Pymm, P., Zeglinski, K., Gouil, Q., Tham, W.-H., & Dietrich, M. H.
Affiliations
  • The University of Melbourne (AU)
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • Australian National University (AU)
Corresponding author
Tham, Wai-Hong
ORCID
Venue
Biochemical Journal
Publisher
openRxiv
Published
2025-12-02
Volume
483
Issue
2
Pages
119-133
ISSN
0264-6021 (ISSN-L)
DOI
10.64898/2025.12.01.691709
PMC
PMC12905498
OpenAlex
W7119025052
Cited by
0
References
1
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
National Health and Medical Research Council (GNT2016908, GNT2001385, GNT2007996)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
Plasmodium falciparum, nanobodies, gamete fusion, transmission blocking, mosquito midgut, fertilisation (biology), crystal structure, monoclonal antibodies, cross-species reactivity, malaria transmission
MeSH terms
Protein Domains, Animals, Antibodies, Protozoan, Antigens, Protozoan, Humans, Models, Molecular, Plasmodium falciparum, Protozoan Proteins, Malaria, Falciparum, Crystallography, X-Ray, Single-Domain Antibodies

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