7st8
Crystal structure of 7H2.2 Fab in complex with SAS1B C-terminal region
Structural highlights
DiseaseASTL_HUMAN The disease may be caused by variants affecting the gene represented in this entry. FunctionASTL_HUMAN Oocyte-specific oolemmal receptor involved in sperm and egg adhesion and fertilization. Plays a role in the polyspermy inhibition. Probably acts as a protease for the post-fertilization cleavage of ZP2. Cleaves the sperm-binding ZP2 at the surface of the zona pellucida after fertilization and cortical granule exocytosis, rendering the zona pellucida unable to support further sperm binding.[UniProtKB:Q6HA09] Publication Abstract from PubMedThe structure of the antigen-binding fragment (Fab) of mouse monoclonal antibody 7H2.2 in complex with a 15-residue fragment from the metalloproteinase sperm acrosomal SLLP1 binding protein (SAS1B), which is a molecular and cellular candidate for both cancer therapy and female contraception, has been determined at 2.75 A resolution by single-crystal X-ray diffraction. Although the crystallization conditions contained the final 148 C-terminal residues of SAS1B, the Fab was observed to crystallize in complex with a 15-residue fragment corresponding to one of only two elements of secondary structure that are predicted to be ordered within the C-terminal region of SAS1B. The antigen forms an amphipathic alpha-helix that binds the 7H2.2 combining site via hydrophilic residues in an epitope that spans the length of the antigen alpha-helix, with only two CH-pi interactions observed along the edge of the interface between the antibody and antigen. Interestingly, the paratope contains two residues mutated away from the germline (YL32F and YH58R), as well as a ProH96-ThrH97-AspH98-AspH99 insertion within heavy chain CDR3. The intact 7H2.2 antibody exhibits high affinity for the SAS1B antigen, with 1:1 binding and nanomolar affinity for both the SAS1B C-terminal construct used for crystallization (3.38 +/- 0.59 nM) and a 15-amino-acid synthetic peptide construct corresponding to the helical antigen observed within the crystal structure (1.60 +/- 0.31 nM). The SAS1B-antibody structure provides the first structural insight into any portion of the subdomain architecture of the C-terminal region of the novel cancer-oocyte tumor surface neoantigen SAS1B and provides a basis for the targeted use of SAS1B. Monoclonal antibody 7H2.2 binds the C-terminus of the cancer-oocyte antigen SAS1B through the hydrophilic face of a conserved amphipathic helix corresponding to one of only two regions predicted to be ordered.,Legg MSG, Gagnon SML, Powell CJ, Boulanger MJ, Li AJJ, Evans SV Acta Crystallogr D Struct Biol. 2022 May 1;78(Pt 5):623-632. doi: , 10.1107/S2059798322003011. Epub 2022 Apr 20. PMID:35503210[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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