8PWH

Atomic structure and conformational variability of the HER2-Trastuzumab-Pertuzumab complex

8PWH の概要

• エントリーDOI: 10.2210/pdb8pwh/pdb
• EMDBエントリー: 17993
• 分子名称: Trastuzumab Fab light chain, Trastuzumab Fab heavy chain, Pertuzumab Fab light chain, ... (7 entities in total)
• 機能のキーワード: erbb-2, pertuzumab, trastuzumab, ternary complex, protein, flexibility, continuous conformation, cryo-em, single particle analysis, structural protein
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 164744.64

構造登録者

Ruedas, R.,Vuillemot, R.,Tubiana, T.,Winter, J.M.,Pieri, L.,Arteni, A.A.,Samson, C.,Jonic, J.,Mathieu, M.,Bressanelli, S. (登録日: 2023-07-20, 公開日: 2024-02-21, 最終更新日: 2024-11-13)

主引用文献

Ruedas, R.,Vuillemot, R.,Tubiana, T.,Winter, J.M.,Pieri, L.,Arteni, A.A.,Samson, C.,Jonic, S.,Mathieu, M.,Bressanelli, S.
Structure and conformational variability of the HER2-trastuzumab-pertuzumab complex.
J.Struct.Biol., 216:108095-108095, 2024

PubMed Abstract: Single particle analysis from cryogenic transmission electron microscopy (cryo-EM) is particularly attractive for complexes for which structure prediction remains intractable, such as antibody-antigen complexes. Here we obtain the detailed structure of a particularly difficult complex between human epidermal growth factor receptor 2 (HER2) and the antigen-binding fragments from two distinct therapeutic antibodies binding to distant parts of the flexible HER2, pertuzumab and trastuzumab (HTP). We highlight the strengths and limitations of current data processing software in dealing with various kinds of heterogeneities, particularly continuous conformational heterogeneity, and in describing the motions that can be extracted from our dataset. Our HTP structure provides a more detailed view than the one previously available for this ternary complex. This allowed us to pinpoint a previously overlooked loop in domain IV that may be involved both in binding of trastuzumab and in HER2 dimerization. This finding may contribute to explain the synergistic anticancer effect of the two antibodies. We further propose that the flexibility of the HTP complex, beyond the difficulties it causes for cryo-EM analysis, actually reflects regulation of HER2 signaling and its inhibition by therapeutic antibodies. Notably we obtain our best data with ultra-thin continuous carbon grids, showing that with current cameras their use to alleviate particle misdistribution is compatible with a protein complex of only 162 kDa. Perhaps most importantly, we provide here a dataset for such a smallish protein complex for further development of software accounting for continuous conformational heterogeneity in cryo-EM images.

PubMed: 38723875
DOI: 10.1016/j.jsb.2024.108095

実験手法

ELECTRON MICROSCOPY (3.17 Å)