4GLY

Human urokinase-type plasminogen activator uPA in complex with the two-disulfide bridge peptide UK504

Summary for 4GLY

• Entry DOI: 10.2210/pdb4gly/pdb
• Related: 3QN7
• Related PRD ID: PRD_001039
• Descriptor: Urokinase-type plasminogen activator, BICYCLIC PEPTIDE INHIBITOR UK504, SULFATE ION, ... (8 entities in total)
• Functional Keywords: serine protease, chymotrypsin fold, urokinase-type plasminogen activator, bicyclic peptide inhibitor, 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: 29962.20

Authors

Buth, S.A.,Leiman, P.G.,Chen, S.,Heinis, C. (deposition date: 2012-08-15, release date: 2013-05-15, Last modification date: 2024-11-06)

Primary citation

Chen, S.,Rentero Rebollo, I.,Buth, S.A.,Morales-Sanfrutos, J.,Touati, J.,Leiman, P.G.,Heinis, C.
Bicyclic Peptide Ligands Pulled out of Cysteine-Rich Peptide Libraries.
J.Am.Chem.Soc., 135:6562-6569, 2013

PubMed Abstract: Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format X(m)CX(n)CX(o)CX(p) are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.

PubMed: 23560397
DOI: 10.1021/ja400461h

Experimental method

X-RAY DIFFRACTION (1.518 Å)