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4Q91

Crystal structure of C16A/K12V/C117V/P134V mutant of human acidic fibroblast growth factor

Summary for 4Q91
Entry DOI10.2210/pdb4q91/pdb
Related1JQZ 1JY0 1RG8 2AFG 3FJE 3FJF 3FJH 3FJK 4Q9G 4Q9P 4QAL
DescriptorFibroblast growth factor 1, FORMIC ACID, PHOSPHATE ION, ... (4 entities in total)
Functional Keywordsbeta-trefoil, growth factor, fgfr binding, heparin binding, extracellular matrix, protein binding
Biological sourceHomo sapiens (human)
Cellular locationSecreted: P05230
Total number of polymer chains2
Total formula weight33570.37
Authors
Xia, X.,Blaber, M. (deposition date: 2014-04-28, release date: 2015-03-11, Last modification date: 2024-02-28)
Primary citationXia, X.,Longo, L.M.,Blaber, M.
Mutation choice to eliminate buried free cysteines in protein therapeutics.
J.Pharm.Sci., 104:566-576, 2015
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.799 Å)
Structure validation

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건을2024-11-13부터공개중

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