4OS6: Crystal structure of urokinase-type plasminogen activator (uPA) complexed with bicyclic peptide UK604 (bicyclic 2)

The disulfide bonds that form between two cysteine residues are important in defining and rigidifying the structures of proteins and peptides. In polypeptides containing multiple cysteine residues, disulfide isomerization can lead to multiple products with different biological activities. Here, we describe the development of a dithiol amino acid (Dtaa) that can form two disulfide bridges at a single amino acid site. Application of Dtaas to a serine protease inhibitor and a nicotinic acetylcholine receptor inhibitor that contain disulfide constraints enhanced their inhibitory activities 40- and 7.6-fold, respectively. X-ray crystallographic and NMR structure analysis show that the peptide ligands containing Dtaas have retained their native tertiary structures. We furthermore show that replacement of two cysteines by Dtaas can avoid the formation of disulfide bond isomers. With these properties, Dtaas are likely to have broad application in the rational design or directed evolution of peptides and proteins with high activity and stability.
PDB ID: 4OS6Download
MMDB ID: 123416
PDB Deposition Date: 2014/2/12
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 1.75  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4OS6: dimeric; determined by author and by software (PISA)
Molecular Components in 4OS6
Label Count Molecule
Proteins (2 molecules)
Urokinase-type Plasminogen Activator(Gene symbol: PLAU)
Molecule annotation
Bicyclic Peptide Uk604 (Bicyclic 2)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB