A Yale-led research team has uncovered how a naturally occurring biological mechanism found in mammals is able to prevent sperm cells from interacting with an egg, preventing fertilization.

The discovery, identified in rodent models, offers a new path for scientific research to help people grappling with infertility issues, while also opening a new line of study for developing contraceptive therapies. The findings appear in the journal Proceedings of the National Academy of Sciences.

“This will have direct implications for infertility and contraception research, especially immuno-infertility and immuno-contraception,” said Steven Tang, an assistant professor of molecular biophysics and biochemistry in Yale’s Faculty of Arts and Sciences and corresponding author of the study.

In the United States, 9% of men and 11% of women of reproductive age experience fertility problems. Some of these problems stem from failures in the proper recognition, adhesion, and fusion of sperm and an egg. A key part of the fertility process involves IZUMO1, a protein on the surface of sperm cells, and JUNO, a receptor on the egg: the IZUMO1-JUNO connection enables sperm and egg recognition and fusion.

One way that the connection can be thwarted is via a sperm antibody called OBF13. This naturally occurring antibody — which was discovered 40 years ago at Osaka University in Japan — can recognize IZUMO1 and disrupt fertilization. But until now, the specifics of this mechanism were unknown.

For the new study, the researchers analyzed the X-ray crystal structure of IZUMO1 as it came in contact with OBF13. The researchers found that OBF13 attaches itself to sperm in such a way that it reconfigures the way sperm come into contact with an egg. The analysis also identified a high-affinity (tightly bonding) variant of OBF13 that potently blocks egg-sperm fertilization.

In addition, the researchers identified key amino acid sites on JUNO that define its ability to bind with IZUMO1. When accessed, these sites are able to bind sperm and egg for fertilization despite interference from OBF13 or its variant.

“In this work, we are reporting the first anti-sperm antibody-antigen complex structure,” Tang said. “We provide high-resolution information that will open avenues for discovering IZUMO1 regulators, guide antibody and small-molecule inhibitor design, and support drug screening for contraceptive development.”

The study’s first author is Yonggang Lu of Osaka University. Masahito Ikawa, also from Osaka University, is the study’s co-author.

The work was supported, in part, by the National Institutes of Health, a David Sokal Innovation Award of Male Contraception Initiative, the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, and a grant from the Takeda Science Foundation. The researchers also made use of facilities at the SLAC National Accelerator Laboratory in California, which is supported by the U.S. Department of Energy’s Office of Science.