8BW0

Structure of CEACAM5 A3-B3 domain in Complex with Tusamitamab Fab

8BW0 の概要

• エントリーDOI: 10.2210/pdb8bw0/pdb
• EMDBエントリー: 16279
• 分子名称: Tusamitamab Fab heavy Chain, Tusamitamab Light Chain, Carcinoembryonic antigen-related cell adhesion molecule 5, ... (6 entities in total)
• 機能のキーワード: ceacam5, tusamitamab, cancer, cell adhesion, cryo-em, small molecular weight, fab, a3-b3, human membrane protein
• 由来する生物種: Mus sp.; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 71783.15

構造登録者

Kumar, A.,Bertrand, T.,Rapisarda, C.,Rak, A. (登録日: 2022-12-06, 公開日: 2024-01-24, 最終更新日: 2024-11-13)

主引用文献

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

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: 39477960
DOI: 10.1038/s41467-024-53746-9

実験手法

ELECTRON MICROSCOPY (3.11 Å)