2N35

Fusion to a Highly Stable Consensus Albumin Binding Domain Allows for Tunable Pharmacokinetics

2N35 の概要

• エントリーDOI: 10.2210/pdb2n35/pdb
• 関連するPDBエントリー: 1GAB 2FS1
• NMR情報: BMRB: 25634
• 分子名称: Albumin binding protein (1 entity in total)
• 機能のキーワード: albumin binding domain, three-helix bundle, de novo protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 5863.73

構造登録者

Gibbs, A.C.,Jacobs, S.A. (登録日: 2015-05-21, 公開日: 2015-09-02, 最終更新日: 2024-05-15)

主引用文献

Jacobs, S.A.,Gibbs, A.C.,Conk, M.,Yi, F.,Maguire, D.,Kane, C.,O'Neil, K.T.
Fusion to a highly stable consensus albumin binding domain allows for tunable pharmacokinetics.
Protein Eng.Des.Sel., 28:385-393, 2015

PubMed Abstract: A number of classes of proteins have been engineered for high stability using consensus sequence design methods. Here we describe the engineering of a novel albumin binding domain (ABD) three-helix bundle protein. The resulting engineered ABD molecule, called ABDCon, is expressed at high levels in the soluble fraction of Escherichia coli and is highly stable, with a melting temperature of 81.5°C. ABDCon binds human, monkey and mouse serum albumins with affinity as high as 61 pM. The solution structure of ABDCon is consistent with the three-helix bundle design and epitope mapping studies enabled a precise definition of the albumin binding interface. Fusion of a 10 kDa scaffold protein to ABDCon results in a long terminal half-life of 60 h in mice and 182 h in cynomolgus monkeys. To explore the link between albumin affinity and in vivo exposure, mutations were designed at the albumin binding interface of ABDCon yielding variants that span an 11 000-fold range in affinity. The PK properties of five such variants were determined in mice in order to demonstrate the tunable nature of serum half-life, exposure and clearance with variations in albumin binding affinity.

PubMed: 26275855
DOI: 10.1093/protein/gzv040

実験手法

SOLUTION NMR