Format

Send to

Choose Destination
Nat Commun. 2018 Oct 26;9(1):4458. doi: 10.1038/s41467-018-06742-9.

Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45.

Author information

1
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, M5G 0A4, ON, Canada.
2
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, 6500 HB, Netherlands.
3
PATH's Malaria Vaccine Initiative, Washington, 20001, DC, USA.
4
LakePharma Inc., Belmont, 94002, CA, USA.
5
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, 20852, MD, USA.
6
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, M5G 0A4, ON, Canada. jean-philippe.julien@sickkids.ca.
7
Departments of Biochemistry and Immunology, University of Toronto, Toronto, M5S 1A8, ON, Canada. jean-philippe.julien@sickkids.ca.

Abstract

Interventions that can block the transmission of malaria-causing Plasmodium falciparum (Pf) between the human host and Anopheles vector have the potential to reduce the incidence of malaria. Pfs48/45 is a gametocyte surface protein critical for parasite development and transmission, and its targeting by monoclonal antibody (mAb) 85RF45.1 leads to the potent reduction of parasite transmission. Here, we reveal how the Pfs48/45 6C domain adopts a (SAG1)-related-sequence (SRS) fold. We structurally delineate potent epitope I and show how mAb 85RF45.1 recognizes an electronegative surface with nanomolar affinity. Analysis of Pfs48/45 sequences reveals that polymorphisms are rare for residues involved at the binding interface. Humanization of rat-derived mAb 85RF45.1 conserved the mode of recognition and activity of the parental antibody, while also improving its thermostability. Our work has implications for the development of transmission-blocking interventions, both through improving vaccine designs and the testing of passive delivery of mAbs in humans.

PMID:
30367064
PMCID:
PMC6203815
DOI:
10.1038/s41467-018-06742-9
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center