4MNV

Crystal structure of bicyclic peptide UK729 bound as an acyl-enzyme intermediate to urokinase-type plasminogen activator (uPA)

4MNV の概要

• エントリーDOI: 10.2210/pdb4mnv/pdb
• 関連するPDBエントリー: 2NWN 3QN7 4GLY 4JK5 4JK6 4MNW 4MNX 4MNY
• 分子名称: Urokinase-type plasminogen activator chain B, acyl-enzyme intermediate of bicyclic peptide UK729, SULFATE ION, ... (8 entities in total)
• 機能のキーワード: acyl-enzyme intermediate, inhibitor, protease, 1, 3, 5-tris(bromomethyl)benzene (tbmb) cyclization, extracellular, 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: 3
• 化学式量合計: 29725.31

構造登録者

Chen, S.,Pojer, F.,Heinis, C. (登録日: 2013-09-11, 公開日: 2014-02-05, 最終更新日: 2024-11-27)

主引用文献

Chen, S.,Bertoldo, D.,Angelini, A.,Pojer, F.,Heinis, C.
Peptide ligands stabilized by small molecules.
Angew.Chem.Int.Ed.Engl., 53:1602-1606, 2014

PubMed Abstract: Bicyclic peptides generated through directed evolution by using phage display offer an attractive ligand format for the development of therapeutics. Being nearly 100-fold smaller than antibodies, they promise advantages such as access to chemical synthesis, efficient diffusion into tissues, and needle-free application. However, unlike antibodies, they do not have a folded structure in solution and thus bind less well. We developed bicyclic peptides with hydrophilic chemical structures at their center to promote noncovalent intramolecular interactions, thereby stabilizing the peptide conformation. The sequences of the peptides isolated by phage display from large combinatorial libraries were strongly influenced by the type of small molecule used in the screen, thus suggesting that the peptides fold around the small molecules. X-ray structure analysis revealed that the small molecules indeed formed hydrogen bonds with the peptides. These noncovalent interactions stabilize the peptide-protein complexes and contribute to the high binding affinity.

PubMed: 24453110
DOI: 10.1002/anie.201309459

実験手法

X-RAY DIFFRACTION (1.8 Å)