6WZL

LY3041658 Fab bound to CXCL7

6WZL の概要

• エントリーDOI: 10.2210/pdb6wzl/pdb
• 関連するPDBエントリー: 6WZJ 6WZK
• 分子名称: LY3041658 Fab heavy chain, LY3041658 Fab light chain, C-X-C motif chemokine 7, ... (6 entities in total)
• 機能のキーワード: cxcr1, cxcr2, neutrophil, nap-2, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 110989.29

構造登録者

Durbin, J.D.,Druzina, Z. (登録日: 2020-05-14, 公開日: 2020-11-25, 最終更新日: 2024-11-06)

主引用文献

Boyles, J.S.,Beidler, C.B.,Strifler, B.A.,Girard, D.S.,Druzina, Z.,Durbin, J.D.,Swearingen, M.L.,Lee, L.N.,Kikly, K.,Chintharlapalli, S.,Witcher, D.R.
Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody.
Mabs, 12:1831880-1831880,

PubMed Abstract: CXCR1 and CXCR2 signaling play a critical role in neutrophil migration, angiogenesis, and tumorigenesis and are therefore an attractive signaling axis to target in a variety of indications. In human, a total of seven chemokines signal through these receptors and comprise the ELRCXC chemokine family, so named because of the conserved ELRCXC N-terminal motif. To fully antagonize CXCR1 and CXCR2 signaling, an effective therapeutic should block either both receptors or all seven ligands, yet neither approach has been fully realized clinically. In this work, we describe the generation and characterization of LY3041658, a humanized monoclonal antibody that binds and neutralizes all seven human and cynomolgus monkey ELRCXC chemokines and three of five mouse and rat ELRCXC chemokines with high affinity. LY3041658 is able to block ELRCXC chemokine-induced Ca mobilization, CXCR2 internalization, and chemotaxis as well as neutrophil mobilization without affecting other neutrophil functions. In addition to the and activity, we characterized the epitope and structural basis for binding in detail through alanine scanning, crystallography, and mutagenesis. Together, these data provide a robust preclinical characterization of LY3041658 for which the efficacy and safety is being evaluated in human clinical trials for neutrophilic skin diseases.

PubMed: 33183151
DOI: 10.1080/19420862.2020.1831880

実験手法

X-RAY DIFFRACTION (2.29 Å)