8BW0
Structure of CEACAM5 A3-B3 domain in Complex with Tusamitamab Fab
Summary for 8BW0
| Entry DOI | 10.2210/pdb8bw0/pdb |
| EMDB information | 16279 |
| Descriptor | Tusamitamab Fab heavy Chain, Tusamitamab Light Chain, Carcinoembryonic antigen-related cell adhesion molecule 5, ... (6 entities in total) |
| Functional Keywords | ceacam5, tusamitamab, cancer, cell adhesion, cryo-em, small molecular weight, fab, a3-b3, human membrane protein |
| Biological source | Mus sp. More |
| Total number of polymer chains | 3 |
| Total formula weight | 71783.15 |
| Authors | Kumar, A.,Bertrand, T.,Rapisarda, C.,Rak, A. (deposition date: 2022-12-06, release date: 2024-01-24, Last modification date: 2024-11-13) |
| Primary citation | Kumar, A.,Duffieux, F.,Gagnaire, M.,Rapisarda, C.,Bertrand, T.,Rak, A. Structural insights into epitope-paratope interactions of a monoclonal antibody targeting CEACAM5-expressing tumors. Nat Commun, 15:9377-9377, 2024 Cited by PubMed Abstract: Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are overexpressed in some tumor types. The antibody-drug conjugate tusamitamab ravtansine specifically recognizes the A3-B3 domains of human CEACAM5 (hCEACAM5). To understand this specificity, here we map the epitope-paratope interface between the A3-B3 domains of hCEACAM5 (hCEACAM5) and the antigen-binding fragment of tusamitamab (tusa Fab). We use hydrogen/deuterium exchange mass spectrometry to identify the tusa Fab paratope, which involves heavy chain (HC) residues 101-109 and light chain residues 48-54 and 88-104. Using surface plasmon resonance, we demonstrate that alanine variants of HC residues 96-108 abolish binding to hCEACAM5, suggesting that these residues are critical for tusa-Fab-antigen complex formation. The cryogenic electron microscopy structure of the hCEACAM5- tusa Fab complex (3.11 Å overall resolution) reveals a discontinuous epitope involving residues in the A3-B3 domains and an N-linked mannose at residue Asn612. Conformational constraints on the epitope-paratope interface enable tusamitamab to target hCEACAM5 and distinguish CEACAM5 from other CEACAMs. PubMed: 39477960DOI: 10.1038/s41467-024-53746-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.11 Å) |
Structure validation
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