4X1P

The crystal structure of mupain-1-17 in complex with murinised human uPA at pH4.6

Summary for 4X1P

• Entry DOI: 10.2210/pdb4x1p/pdb
• Related: 4N1Q 4N1R 4N1S 4X0W 4X1N
• Descriptor: Urokinase-type plasminogen activator, MUPAIN-1-17, SULFATE ION, ... (6 entities in total)
• Functional Keywords: serine protease, peptidic inhibitor, upa, 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: 29594.64

Authors

Jiang, L.,Zhao, B.,Xu, P.,Andreasen, P.,Huang, M. (deposition date: 2014-11-25, release date: 2015-10-21, Last modification date: 2017-10-18)

Primary citation

Jiang, L.,Zhao, B.,Xu, P.,Srensen, H.P.,Jensen, J.K.,Christensen, A.,Hosseini, M.,Nielsen, N.C.,Jensen, K.J.,Andreasen, P.A.,Huang, M.
Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues.
Int.J.Biochem.Cell Biol., 62:88-92, 2015

PubMed Abstract: Two isomeric piperidine derivatives (meta and para isomers) were used as arginine mimics in the P1 position of a cyclic peptidic inhibitor (CPAYSRYLDC) of urokinase-type plasminogen activator. The two resulting cyclic peptides showed vastly different affinities (∼70 fold) to the target enzyme. X-ray crystal structure analysis showed that the two P1 residues were inserted into the S1 specificity pocket in indistinguishable manners. However, the rest of the peptides bound in entirely different ways on the surface of the enzyme, and the two peptides have different conformations, despite the highly similar sequence. These results demonstrate how the subtle difference in P1 residue can dictate the exosite interactions and the potencies of peptidic inhibitors, and highlight the importance of the P1 residue for protease inhibition. This study provides important information for the development of peptidic agents for pharmacological intervention.

PubMed: 25744057
DOI: 10.1016/j.biocel.2015.02.016

Experimental method

X-RAY DIFFRACTION (1.6 Å)