4q91 | pdb_00004q91

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

spinqualitylabelsall models 4q91, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4q91 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FMT, PO4 Related: 2afg, 1jqz, 1rg8, 4q9g, 4q9p, 4qal, 1jy0, 3fjh, 3fjf, 3fje, 3fjk Resources: FirstGlance, OCA, RCSB, PDBsum Function [FGF1_HUMAN] Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Publication Abstract from PubMed 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. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:566-576, 2015. Mutation choice to eliminate buried free cysteines in protein therapeutics.,Xia X, Longo LM, Blaber M J Pharm Sci. 2015 Feb;104(2):566-76. doi: 10.1002/jps.24188. Epub 2014 Oct 13. PMID:25312595 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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