Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

Melanie H. Dietrich; Jill Chmielewski; Li-Jin Chan; Li Lynn Tan; Amy Adair; Frankie M.T. Lyons; Mikha Gabriela; Sash Lopaticki; Toby A Dite; Laura F. Dagley; Lucia Pazzagli; Priya Gupta; Mohd Kamil; Ashley M. Vaughan; Rattanaporn Rojrung; Anju Abraham; Ramin Mazhari; Rhea Longley; Kathleen Zeglinski; Quentin Gouil; Ivo Mueller; Stewart A Fabb; Rekha Shandre-Mugan; Colin W Pouton; Alisa Glukhova; Shabih Shakeel; Wai Hong Tham

doi:10.1126/science.ady0241

Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

Melanie H. Dietrich, Jill Chmielewski, Li-Jin Chan, Li Lynn Tan, Amy Adair, Frankie M.T. Lyons, Mikha Gabriela, Sash Lopaticki, Toby A Dite, Laura F. Dagley, Lucia Pazzagli, Priya Gupta, Mohd Kamil, Ashley M. Vaughan, Rattanaporn Rojrung, Anju Abraham, Ramin Mazhari, Rhea Longley, Kathleen Zeglinski, Quentin GouilIvo Mueller, Stewart A Fabb, Rekha Shandre-Mugan, Colin W Pouton, Alisa Glukhova, Shabih Shakeel, Wai Hong Tham^*

^*Corresponding author for this work

Division of Biomedical Science & Biochemistry

Research output: Contribution to journal › Article › peer-review

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Abstract

Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo–electron microscopy structure of endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation, reduced transmission and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from mRNA–lipid nanoparticle immunizations blocked parasite transmission.

Original language	English
Article number	1106
Pages (from-to)	1-16
Number of pages	16
Journal	Science
Volume	389
Issue number	6765
DOIs	https://doi.org/10.1126/science.ady0241
Publication status	E-pub ahead of print - 31 Jul 2025

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Dietrich, M. H., Chmielewski, J., Chan, L.-J., Tan, L. L., Adair, A., Lyons, F. M. T., Gabriela, M., Lopaticki, S., Dite, T. A., Dagley, L. F., Pazzagli, L., Gupta, P., Kamil, M., Vaughan, A. M., Rojrung, R., Abraham, A., Mazhari, R., Longley, R., Zeglinski, K., ... Tham, W. H. (2025). Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex. Science, 389(6765), 1-16. Article 1106. Advance online publication. https://doi.org/10.1126/science.ady0241

@article{fde05f7c38a9442d888f551ca148233e,

title = "Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex",

abstract = "Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo–electron microscopy structure of endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation, reduced transmission and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from mRNA–lipid nanoparticle immunizations blocked parasite transmission.",

author = "Dietrich, \{Melanie H.\} and Jill Chmielewski and Li-Jin Chan and Tan, \{Li Lynn\} and Amy Adair and Lyons, \{Frankie M.T.\} and Mikha Gabriela and Sash Lopaticki and Dite, \{Toby A\} and Dagley, \{Laura F.\} and Lucia Pazzagli and Priya Gupta and Mohd Kamil and Vaughan, \{Ashley M.\} and Rattanaporn Rojrung and Anju Abraham and Ramin Mazhari and Rhea Longley and Kathleen Zeglinski and Quentin Gouil and Ivo Mueller and Fabb, \{Stewart A\} and Rekha Shandre-Mugan and Pouton, \{Colin W\} and Alisa Glukhova and Shabih Shakeel and Tham, \{Wai Hong\}",

note = "{\textcopyright} 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2025",

month = jul,

day = "31",

doi = "10.1126/science.ady0241",

language = "English",

volume = "389",

pages = "1--16",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6765",

}

Dietrich, MH, Chmielewski, J, Chan, L-J, Tan, LL, Adair, A, Lyons, FMT, Gabriela, M, Lopaticki, S, Dite, TA, Dagley, LF, Pazzagli, L, Gupta, P, Kamil, M, Vaughan, AM, Rojrung, R, Abraham, A, Mazhari, R, Longley, R, Zeglinski, K, Gouil, Q, Mueller, I, Fabb, SA, Shandre-Mugan, R, Pouton, CW, Glukhova, A, Shakeel, S & Tham, WH 2025, 'Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex', Science, vol. 389, no. 6765, 1106, pp. 1-16. https://doi.org/10.1126/science.ady0241

TY - JOUR

T1 - Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

AU - Dietrich, Melanie H.

AU - Chmielewski, Jill

AU - Chan, Li-Jin

AU - Tan, Li Lynn

AU - Adair, Amy

AU - Lyons, Frankie M.T.

AU - Gabriela, Mikha

AU - Lopaticki, Sash

AU - Dite, Toby A

AU - Dagley, Laura F.

AU - Pazzagli, Lucia

AU - Gupta, Priya

AU - Kamil, Mohd

AU - Vaughan, Ashley M.

AU - Rojrung, Rattanaporn

AU - Abraham, Anju

AU - Mazhari, Ramin

AU - Longley, Rhea

AU - Zeglinski, Kathleen

AU - Gouil, Quentin

AU - Mueller, Ivo

AU - Fabb, Stewart A

AU - Shandre-Mugan, Rekha

AU - Pouton, Colin W

AU - Glukhova, Alisa

AU - Shakeel, Shabih

AU - Tham, Wai Hong

PY - 2025/7/31

Y1 - 2025/7/31

N2 - Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo–electron microscopy structure of endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation, reduced transmission and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from mRNA–lipid nanoparticle immunizations blocked parasite transmission.

AB - Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo–electron microscopy structure of endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation, reduced transmission and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from mRNA–lipid nanoparticle immunizations blocked parasite transmission.

UR - https://www.scopus.com/pages/publications/105015504901

U2 - 10.1126/science.ady0241

DO - 10.1126/science.ady0241

M3 - Article

SN - 0036-8075

VL - 389

SP - 1

EP - 16

JO - Science

JF - Science

IS - 6765

M1 - 1106

ER -

Cryo-EM structure of endogenous Plasmodium falciparum Pfs230 and Pfs48/45 fertilization complex

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