4Q9P

Crystal structure of C16T/K12V/C117V/P134V mutant of human acidic fibroblast growth factor

4Q9P の概要

• エントリーDOI: 10.2210/pdb4q9p/pdb
• 関連するPDBエントリー: 1JQZ 1JY0 1RG8 2AFG 3FJE 3FJF 3FJH 3FJK 4Q91 4Q9G 4QAL
• 分子名称: Fibroblast growth factor 1 (2 entities in total)
• 機能のキーワード: beta-trefoil, growth factor, fgfr binding, heparin binding, extracellular matrix, protein binding
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P05230
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33305.32

構造登録者

Blaber, M.,Xia, X. (登録日: 2014-05-01, 公開日: 2015-03-11, 最終更新日: 2024-02-28)

主引用文献

Xia, X.,Longo, L.M.,Blaber, M.
Mutation choice to eliminate buried free cysteines in protein therapeutics.
J.Pharm.Sci., 104:566-576, 2015

PubMed Abstract: Buried free-cysteine (Cys) residues can contribute to an irreversible unfolding pathway that promotes protein aggregation, increases immunogenic potential, and significantly reduces protein functional half-life. Consequently, mutation of buried free-Cys residues can result in significant improvement in the storage, reconstitution, and pharmacokinetic properties of protein-based therapeutics. Mutational design to eliminate buried free-Cys residues typically follows one of two common heuristics: either substitution by Ser (polar and isosteric), or substitution by Ala or Val (hydrophobic); however, a detailed structural and thermodynamic understanding of Cys mutations is lacking. We report a comprehensive structure and stability study of Ala, Ser, Thr, and Val mutations at each of the three buried free-Cys positions (Cys16, Cys83, and Cys117) in fibroblast growth factor-1. Mutation was almost universally destabilizing, indicating a general optimization for the wild-type Cys, including van der Waals and H-bond interactions. Structural response to Cys mutation characteristically involved changes to maintain, or effectively substitute, local H-bond interactions-by either structural collapse to accommodate the smaller oxygen radius of Ser/Thr, or conversely, expansion to enable inclusion of novel H-bonding solvent. Despite the diverse structural effects, the least destabilizing average substitution at each position was Ala, and not isosteric Ser.

PubMed: 25312595
DOI: 10.1002/jps.24188

実験手法

X-RAY DIFFRACTION (1.8 Å)