4MID

Crystal Structure of Activin A/BMP2 chimera

4MID の概要

• エントリーDOI: 10.2210/pdb4mid/pdb
• 分子名称: AB204 Activin A/BMP2 chimera (2 entities in total)
• 機能のキーワード: cysteine knot, cytokine, actrii, bmpria, secreted
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13090.08

構造登録者

Esquivies, L. (登録日: 2013-08-30, 公開日: 2014-05-07, 最終更新日: 2024-11-20)

主引用文献

Yoon, B.H.,Esquivies, L.,Ahn, C.,Gray, P.C.,Ye, S.K.,Kwiatkowski, W.,Choe, S.
An Activin A/BMP2 Chimera, AB204, Displays Bone-Healing Properties Superior to Those of BMP2.
J.Bone Miner.Res., 29:1950-1959, 2014

PubMed Abstract: Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10-fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2-like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100-fold greater than that of BMP2. The structure also led to our identification of a single Activin A-derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non-union bone fractures.

PubMed: 24692083
DOI: 10.1002/jbmr.2238

実験手法

X-RAY DIFFRACTION (2.139 Å)