6QBA
Crystal Structure of Retinol-Binding Protein 4 (RBP4) in complex with non-retinoid ligand A1120 and engineered binding scaffold
6QBA の概要
エントリーDOI | 10.2210/pdb6qba/pdb |
分子名称 | Retinol-binding protein 4, DNA-binding protein 7a, 2-[({4-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)amino]benzoic acid, ... (8 entities in total) |
機能のキーワード | lipocalin, rbp4, retinol binding protein, transport protein |
由来する生物種 | Homo sapiens (Human) 詳細 |
タンパク質・核酸の鎖数 | 2 |
化学式量合計 | 29281.70 |
構造登録者 | Mlynek, G.,Brey, C.U.,Djinovic-Carugo, K.,Puehringer, D. (登録日: 2018-12-20, 公開日: 2020-06-03, 最終更新日: 2024-11-06) |
主引用文献 | Zajc, C.U.,Dobersberger, M.,Schaffner, I.,Mlynek, G.,Puhringer, D.,Salzer, B.,Djinovic-Carugo, K.,Steinberger, P.,De Sousa Linhares, A.,Yang, N.J.,Obinger, C.,Holter, W.,Traxlmayr, M.W.,Lehner, M. A conformation-specific ON-switch for controlling CAR T cells with an orally available drug. Proc.Natl.Acad.Sci.USA, 117:14926-14935, 2020 Cited by PubMed Abstract: Molecular ON-switches in which a chemical compound induces protein-protein interactions can allow cellular function to be controlled with small molecules. ON-switches based on clinically applicable compounds and human proteins would greatly facilitate their therapeutic use. Here, we developed an ON-switch system in which the human retinol binding protein 4 (hRBP4) of the lipocalin family interacts with engineered hRBP4 binders in a small molecule-dependent manner. Two different protein scaffolds were engineered to bind to hRBP4 when loaded with the orally available small molecule A1120. The crystal structure of an assembled ON-switch shows that the engineered binder specifically recognizes the conformational changes induced by A1120 in two loop regions of hRBP4. We demonstrate that this conformation-specific ON-switch is highly dependent on the presence of A1120, as demonstrated by an ∼500-fold increase in affinity upon addition of the small molecule drug. Furthermore, the ON-switch successfully regulated the activity of primary human CAR T cells in vitro. We anticipate that lipocalin-based ON-switches have the potential to be broadly applied for the safe pharmacological control of cellular therapeutics. PubMed: 32554495DOI: 10.1073/pnas.1911154117 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (1.8 Å) |
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