4MNW

Crystal structure of urokinase-type plasminogen activator (uPA) complexed with bicyclic peptide UK749

Summary for 4MNW

• Entry DOI: 10.2210/pdb4mnw/pdb
• Related: 2NWN 3QN7 4GLY 4JK5 4JK6 4MNV 4MNX 4MNY
• Related PRD ID: PRD_001166
• Descriptor: Urokinase-type plasminogen activator chain B, bicyclic peptide UK749, SULFATE ION, ... (7 entities in total)
• Functional Keywords: competitive inhibitor, bicyclic peptide, inhibitor, protease, 1, 3, 5-tris(bromomethyl)benzene (tbmb) cyclization, extracellular, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00749
• Total number of polymer chains: 2
• Total formula weight: 30267.76

Authors

Chen, S.,Pojer, F.,Heinis, C. (deposition date: 2013-09-11, release date: 2014-02-05, Last modification date: 2024-11-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.49 Å)