9MYL | pdb_00009myl

Fertilization IZUMO1 Protein Ectodomain in Complex with Anti-sperm Antibody OBF13

PDB DOI: https://doi.org/10.2210/pdb9MYL/pdb

Classification: CELL ADHESION
Organism(s): Mus musculus
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2025-01-22 Released: 2025-03-19
Deposition Author(s): Tang, S.
Funding Organization(s): National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.18 ?
R-Value Free:
0.263 (Depositor), 0.269 (DCC)
R-Value Work:
0.212 (Depositor), 0.220 (DCC)
R-Value Observed:
0.214 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Allosteric inhibition of the IZUMO1-JUNO fertilization complex by the naturally occurring antisperm antibody OBF13.

Lu, Y., Ikawa, M., Tang, S.

(2025) Proc Natl Acad Sci U S A 122: e2425952122-e2425952122

PubMed: 40042902 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1073/pnas.2425952122
Primary Citation of Related Structures:
9MYL, 9MYM

PubMed Abstract:
Sperm IZUMO1 binds to egg JUNO, and this interaction is essential for mammalian fertilization. Isolated from a female mouse immunized with syngeneic sperm, the antisperm antibody OBF13 recognizes IZUMO1 and inhibits murine fertilization. How OBF13 interferes with sperm-egg interactions was unknown. Here, we present the X-ray crystal structure of IZUMO1 in complex with OBF13. OBF13 binds to the apex of the four-helix domain of IZUMO1, distant from the JUNO-binding site. Our crystal structure of OBF13-bound IZUMO1 resembles apo-IZUMO1 and differs from the structure of IZUMO1 in complex with JUNO. We identify that OBF13 carries a low level of somatic hypermutation, and through deep mutational scanning, we engineer an affinity-enhanced OBF13 variant. This OBF13 variant single-chain fragment variable decreases the apparent affinity of IZUMO1 for membrane-bound murine JUNO and blocks the binding of acrosome-reacted sperm to eggs, thereby preventing fertilization. We propose allostery between the OBF13 epitope and the JUNO-binding site. OBF13 inhibits a conformational change in IZUMO1, preventing fusion-competent sperm from adhering to murine eggs during fertilization. Surprisingly, murine IZUMO1 binds to hamster JUNO with an affinity ~20-fold higher than to murine JUNO. The decreased affinity caused by OBF13 of murine IZUMO1 for hamster JUNO is sufficient for murine sperm to bind to and fuse with hamster eggs. Our studies provide a structural and mechanistic framework for species-specific, allosteric inhibition of IZUMO1 by a naturally occurring antisperm antibody and offer insights into the development of immunocontraceptives.

Organizational Affiliation

Premium Research Institute for Human Metaverse Medicine, Osaka University, Suita, Osaka 565-0871, Japan.

Macromolecule Content

Total Structure Weight: 149.57 kDa
Atom Count: 9,194
Modelled Residue Count: 1,256
Deposited Residue Count: 1,336
Unique protein chains: 3

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Izumo sperm-egg fusion protein 1	A [auth C], B [auth D]	238	Mus musculus	Mutation(s): 0 Gene Names: Izumo1
UniProt
Find proteins for Q9D9J7 (Mus musculus) Explore Q9D9J7 Go to UniProtKB: Q9D9J7
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9D9J7
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain B [auth D]	Go to GlyGen: Q9D9J7-1
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Anti-sperm antibody OBF13 heavy chain	C [auth H], E [auth A]	217	Mus musculus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Anti-sperm antibody OBF13 light chain	D [auth L], F [auth B]	213	Mus musculus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain I [auth D] SDF format, chain G [auth C] MOL2 format, chain I [auth D] MOL2 format, chain G [auth C] mmCIF format, chain I [auth D] mmCIF format, chain G [auth C]	G [auth C], I [auth D]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain G [auth C] Focus chain I [auth D] Interactions & Density Focus chain G [auth C] Focus chain I [auth D]
PRO Query on PRO Download Ideal Coordinates CCD File SDF format, chain H [auth C] SDF format, chain J [auth D] MOL2 format, chain H [auth C] MOL2 format, chain J [auth D] mmCIF format, chain H [auth C] mmCIF format, chain J [auth D]	H [auth C], J [auth D]	PROLINE C₅ H₉ N O₂ ONIBWKKTOPOVIA-BYPYZUCNSA-N		Interactions Focus chain H [auth C] Focus chain J [auth D] Interactions & Density Focus chain H [auth C] Focus chain J [auth D]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain K [auth L] SDF format, chain L [auth A] MOL2 format, chain K [auth L] MOL2 format, chain L [auth A] mmCIF format, chain K [auth L] mmCIF format, chain L [auth A]	K [auth L], L [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain K [auth L] Focus chain L [auth A] Interactions & Density Focus chain K [auth L] Focus chain L [auth A]