5ICZ

Cetuximab Fab in complex with GQFDLSTRRLKG peptide

5ICZ の概要

• エントリーDOI: 10.2210/pdb5icz/pdb
• 関連するPDBエントリー: 4GW1 4HR8 5ESQ 5ETU 5EUK 5F88 5FF6 5HPM 5HYQ 5I2I 5ICX 5ICY 5ID0 5ID1
• 分子名称: Cetuximab Fab light chain, Cetuximab Fab heavy chain, Meditope, ... (5 entities in total)
• 機能のキーワード: antibody, anti-egfr, immune system
• 由来する生物種: MUS MUSCULUS, HOMO SAPIENS (mouse, human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 97262.42

構造登録者

Bzymek, K.P.,Williams, J.C. (登録日: 2016-02-23, 公開日: 2016-06-15, 最終更新日: 2024-11-20)

主引用文献

Bzymek, K.P.,Ma, Y.,Avery, K.A.,Horne, D.A.,Williams, J.C.
Cyclization strategies of meditopes: affinity and diffraction studies of meditope-Fab complexes.
Acta Crystallogr F Struct Biol Commun, 72:434-442, 2016

PubMed Abstract: Recently, a unique binding site for a cyclic 12-residue peptide was discovered within a cavity formed by the light and heavy chains of the cetuximab Fab domain. In order to better understand the interactions that drive this unique complex, a number of variants including the residues within the meditope peptide and the antibody, as well as the cyclization region of the meditope peptide, were created. Here, multiple crystal structures of meditope peptides incorporating different cyclization strategies bound to the central cavity of the cetuximab Fab domain are presented. The affinity of each cyclic derivative for the Fab was determined by surface plasmon resonance and correlated to structural differences. Overall, it was observed that the disulfide bond used to cyclize the peptide favorably packs against a hydrophobic `pocket' and that amidation and acetylation of the original disulfide meditope increased the overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with serines and thus creating a linear peptide reduced the affinity over 50-fold, with much of this difference being reflected in a decrease in the on-rate. Other cyclization methods, including the formation of a lactam, reduced the affinity but not to the extent of the linear peptide. Collectively, the structural and kinetic data presented here indicate that small perturbations introduced by different cyclization strategies can significantly affect the affinity of the meditope-Fab complex.

PubMed: 27303895
DOI: 10.1107/S2053230X16007202

実験手法

X-RAY DIFFRACTION (2.55 Å)