4JK5

Human urokinase-type Plasminogen Activator (uPA) in complex with a bicyclic peptide inhibitor (UK18-D-Ser)

4JK5 の概要

• エントリーDOI: 10.2210/pdb4jk5/pdb
• 関連するPDBエントリー: 3QN7 4GLY
• 関連するBIRD辞書のPRD_ID: PRD_000926
• 分子名称: Urokinase-type plasminogen activator, bicyclic peptide UK18-D-Ser, uPA inhibitor, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: serine protease, chymotrypsin fold, urokinase-type plasminogen activator, bicyclic peptide inhibitor, d-amino acid, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P00749
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30501.82

構造登録者

Buth, S.A.,Leiman, P.G.,Chen, S.,Heinis, C. (登録日: 2013-03-09, 公開日: 2013-07-17, 最終更新日: 2024-11-20)

主引用文献

Chen, S.,Gfeller, D.,Buth, S.A.,Michielin, O.,Leiman, P.G.,Heinis, C.
Improving binding affinity and stability of Peptide ligands by substituting glycines with d-amino acids.
Chembiochem, 14:1316-1322, 2013

PubMed Abstract: Improving the binding affinity and/or stability of peptide ligands often requires testing of large numbers of variants to identify beneficial mutations. Herein we propose a type of mutation that promises a high success rate. In a bicyclic peptide inhibitor of the cancer-related protease urokinase-type plasminogen activator (uPA), we observed a glycine residue that has a positive ϕ dihedral angle when bound to the target. We hypothesized that replacing it with a D-amino acid, which favors positive ϕ angles, could enhance the binding affinity and/or proteolytic resistance. Mutation of this specific glycine to D-serine in the bicyclic peptide indeed improved inhibitory activity (1.75-fold) and stability (fourfold). X-ray-structure analysis of the inhibitors in complex with uPA showed that the peptide backbone conformation was conserved. Analysis of known cyclic peptide ligands showed that glycine is one of the most frequent amino acids, and that glycines with positive ϕ angles are found in many protein-bound peptides. These results suggest that the glycine-to-D-amino acid mutagenesis strategy could be broadly applied.

PubMed: 23828687
DOI: 10.1002/cbic.201300228

実験手法

X-RAY DIFFRACTION (1.55 Å)