5HHC

Crystal Structure of Chemically Synthesized Heterochiral {RFX037 plus VEGF-A} Protein Complex in space group P21/n

5HHC の概要

• エントリーDOI: 10.2210/pdb5hhc/pdb
• 関連するPDBエントリー: 4GLN
• 分子名称: Vascular endothelial growth factor A, D- Vascular endothelial growth factor-A, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: heterochiral protein-protein complex, d-protein antagonist, growth factor-inhibitor complex, racemic protein crystallography, de novo protein
• 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: 39696.48

構造登録者

Uppalapati, M.,Lee, D.J.,Mandal, K.,Kent, S.B.H.,Sidhu, S. (登録日: 2016-01-10, 公開日: 2016-03-09, 最終更新日: 2023-11-15)

主引用文献

Uppalapati, M.,Lee, D.J.,Mandal, K.,Li, H.,Miranda, L.P.,Lowitz, J.,Kenney, J.,Adams, J.J.,Ault-Riche, D.,Kent, S.B.,Sidhu, S.S.
A Potent d-Protein Antagonist of VEGF-A is Nonimmunogenic, Metabolically Stable, and Longer-Circulating in Vivo.
Acs Chem.Biol., 11:1058-1065, 2016

PubMed Abstract: Polypeptides composed entirely of d-amino acids and the achiral amino acid glycine (d-proteins) inherently have in vivo properties that are proposed to be near-optimal for a large molecule therapeutic agent. Specifically, d-proteins are resistant to degradation by proteases and are anticipated to be nonimmunogenic. Furthermore, d-proteins are manufactured chemically and can be engineered to have other desirable properties, such as improved stability, affinity, and pharmacokinetics. Thus, a well-designed d-protein therapeutic would likely have significant advantages over l-protein drugs. Toward the goal of developing d-protein therapeutics, we previously generated RFX001.D, a d-protein antagonist of natural vascular endothelial growth factor A (VEGF-A) that inhibited binding to its receptor. However, RFX001.D is unstable at physiological temperatures (Tm = 33 °C). Here, we describe RFX037.D, a variant of RFX001.D with extreme thermal stability (Tm > 95 °C), high affinity for VEGF-A (Kd = 6 nM), and improved receptor blocking. Comparison of the two enantiomeric forms of RFX037 revealed that the d-protein is more stable in mouse, monkey, and human plasma and has a longer half-life in vivo in mice. Significantly, RFX037.D was nonimmunogenic in mice, whereas the l-enantiomer generated a strong immune response. These results confirm the potential utility of synthetic d-proteins as alternatives to therapeutic antibodies.

PubMed: 26745345
DOI: 10.1021/acschembio.5b01006

実験手法

X-RAY DIFFRACTION (2.1 Å)