5DWU

Beta common receptor in complex with a Fab

5DWU の概要

• エントリーDOI: 10.2210/pdb5dwu/pdb
• 分子名称: Cytokine receptor common subunit beta, Fab - Heavy Chain, Fab - Light Chain, ... (5 entities in total)
• 機能のキーワード: fab complex, antigen recognition, therapeutic antibody, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 96608.93

構造登録者

Dhagat, U.,Parker, M.W. (登録日: 2015-09-23, 公開日: 2015-12-30, 最終更新日: 2024-10-30)

主引用文献

Panousis, C.,Dhagat, U.,Edwards, K.M.,Rayzman, V.,Hardy, M.P.,Braley, H.,Gauvreau, G.M.,Hercus, T.R.,Smith, S.,Sehmi, R.,McMillan, L.,Dottore, M.,McClure, B.J.,Fabri, L.J.,Vairo, G.,Lopez, A.F.,Parker, M.W.,Nash, A.D.,Wilson, N.J.,Wilson, M.J.,Owczarek, C.M.
CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common beta chain of the IL-3, GM-CSF and IL-5 receptors.
Mabs, 8:436-453, 2016

PubMed Abstract: The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (βc, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).

PubMed: 26651396
DOI: 10.1080/19420862.2015.1119352

実験手法

X-RAY DIFFRACTION (3.97 Å)