5TRU

Structure of the first-in-class checkpoint inhibitor Ipilimumab bound to human CTLA-4

5TRU の概要

• エントリーDOI: 10.2210/pdb5tru/pdb
• 分子名称: Ipilimumab Fab light chain, Ipilimumab Fab heavy chain, Cytotoxic T-lymphocyte protein 4 (3 entities in total)
• 機能のキーワード: antibody, complex, fab, immune system
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : P16410
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 120693.16

構造登録者

Ramagopal, U.A.,Liu, W.,Garrett-Thomson, S.C.,Yan, Q.,Srinivasan, M.,Wong, S.C.,Bell, A.,Mankikar, S.,Rangan, V.S.,Deshpande, S.,Bonanno, J.B.,Korman, A.J.,Almo, S.C. (登録日: 2016-10-27, 公開日: 2017-05-10, 最終更新日: 2024-11-20)

主引用文献

Ramagopal, U.A.,Liu, W.,Garrett-Thomson, S.C.,Bonanno, J.B.,Yan, Q.,Srinivasan, M.,Wong, S.C.,Bell, A.,Mankikar, S.,Rangan, V.S.,Deshpande, S.,Korman, A.J.,Almo, S.C.
Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.
Proc. Natl. Acad. Sci. U.S.A., 114:E4223-E4232, 2017

PubMed Abstract: Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 Å resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

PubMed: 28484017
DOI: 10.1073/pnas.1617941114

実験手法

X-RAY DIFFRACTION (3 Å)