2JIX

Crystal structure of ABT-007 FAB fragment with the soluble domain of EPO receptor

2JIX の概要

• エントリーDOI: 10.2210/pdb2jix/pdb
• 関連するPDBエントリー: 1CN4 1EBA 1EBP 1EER 1ERN
• 分子名称: ABT-007 FAB FRAGMENT, ERYTHROPOIETIN RECEPTOR (3 entities in total)
• 機能のキーワード: immune system, receptor, transmembrane, receptor soluble domain, antibody, receptor-immune system complex, receptor/immune system
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 213148.86

構造登録者

Liu, Z.,Stoll, V.S.,DeVries, P.,Jakob, C.G.,Xie, N.,Simmer, R.L.,Lacy, S.E.,Egan, D.A.,Harlan, J.E.,Lesniewski, R.R.,Reilly, E.B. (登録日: 2007-07-02, 公開日: 2007-07-10, 最終更新日: 2024-10-23)

主引用文献

Liu, Z.,Stoll, V.S.,Devries, P.,Jakob, C.G.,Xie, N.,Simmer, R.L.,Lacy, S.E.,Egan, D.A.,Harlan, J.E.,Lesniewski, R.R.,Reilly, E.B.
A Potent Erythropoietin-Mimicking Human Antibody Interacts Through a Novel Binding Site.
Blood, 110:2408-, 2007

PubMed Abstract: Recombinant human erythropoietin (rHu-EPO) is used to treat anemia by activating the erythropoietin receptor (EPOR) in erythroid progenitor cells, leading to proliferation and differentiation into mature red blood cells. To allow less frequent dosing, a hyperglycosylated version of EPO has been developed with a longer half-life. In principle, an agonistic antibody targeting EPOR would offer an even longer half-life, support robust monthly dosing, and, unlike EPO products, reduce the risk of pure red cell aplasia. The efficiency of signaling and corresponding potency of previously reported antibody mimics are generally suboptimal compared with EPO and not suitable for clinical use. Here we describe a potent, fully human, agonistic antibody (ABT007) targeting EPOR that supports potent, more sustained, and less pulsatile elevation of hematocrit in a human EPOR-expressing transgenic mouse model compared with standard doses of rHu-EPO while requiring less frequent dosing. Resolution of the crystal structure of the EPOR extracellular domain (ECD) complexed to the ABT007 Fab fragment, determined at 0.32 nm, identifies a binding site that is consistent with a novel mechanism of receptor activation based on a unique antibody-imposed conformational change. These results demonstrate that a symmetric molecule can serve as a potent activator of the EPOR.

PubMed: 17620453
DOI: 10.1182/BLOOD-2007-04-083998

実験手法

X-RAY DIFFRACTION (3.2 Å)