1TZH

Crystal Structure of the Fab YADS1 Complexed with h-VEGF

1TZH の概要

• エントリーDOI: 10.2210/pdb1tzh/pdb
• 関連するPDBエントリー: 1tzi
• 分子名称: Vascular endothelial growth factor A, Fab YADS1 Light Chain, Fab YADS1 Heavy Chain, ... (4 entities in total)
• 機能のキーワード: phage display, antibody library, protein engineering, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P15692
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 118570.13

構造登録者

Fellouse, F.A.,Wiesmann, C.,Sidhu, S.S. (登録日: 2004-07-09, 公開日: 2004-08-31, 最終更新日: 2024-11-13)

主引用文献

Fellouse, F.A.,Wiesmann, C.,Sidhu, S.S.
Synthetic antibodies from a four-amino-acid code: A dominant role for tyrosine in antigen recognition
Proc.Natl.Acad.Sci.USA, 101:12467-12472, 2004

PubMed Abstract: Antigen-binding fragments (Fabs) with synthetic antigen-binding sites were isolated from phage-displayed libraries with restricted complementarity-determining region (CDR) diversity. Libraries were constructed such that solvent-accessible CDR positions were randomized with a degenerate codon that encoded for only four amino acids (tyrosine, alanine, aspartate, and serine). Nonetheless, high-affinity Fabs (K(d) = 2-10 nM) were isolated against human vascular endothelial growth factor (hVEGF), and the crystal structures were determined for two distinct Fab-hVEGF complexes. The structures revealed that antigen recognition was mediated primarily by tyrosine side chains, which accounted for 71% of the Fab surface area that became buried upon binding to hVEGF. In contrast, aspartate residues within the CDRs were almost entirely excluded from the binding interface. Alanine and serine residues did not make many direct contacts with antigen, but they allowed for space and conformational flexibility and thus played an auxiliary role in facilitating productive contacts between tyrosine and antigen. Tyrosine side chains were capable of mediating most of the contacts necessary for high-affinity antigen recognition, and, thus, it seems likely that the overabundance of tyrosine in natural antigen-binding sites is a consequence of the side chain being particularly well suited for making productive contacts with antigen. The findings shed light on the basic principles governing the evolution of natural immune repertoires and should also aid the development of improved synthetic antibody libraries.

PubMed: 15306681
DOI: 10.1073/pnas.0401786101

実験手法

X-RAY DIFFRACTION (2.6 Å)