PDBsum entry 4x0w

Hydrolase inhibitor/hydrolase

PDB id: 4x0w

Contents

Protein chain

247 a.a.

Ligands

CYS-PRO-ALA-TYR-SER-DAL-TYR-LEU-ASP-CYS

MRZ

SO4

Waters ×29

PDB id:

4x0w

Name:

Hydrolase inhibitor/hydrolase

Title:

The crystal structure of mupain-1-17 in complex with murinised human upa

Structure:

Mupain-1-17. Chain: p. Engineered: yes. Urokinase-type plasminogen activator. Chain: u. Fragment: unp residues 179-425. Synonym: upa. Engineered: yes. Mutation: yes

Source:

Synthetic: yes. Synthetic construct. Organism_taxid: 32630. Homo sapiens. Human. Organism_taxid: 9606. Gene: plau. Expressed in: komagataella pastoris. Expression_system_taxid: 4922

Resolution:

2.10Å R-factor: 0.238 R-free: 0.272

Authors:

L.Jiang,B.Zhao,P.Xu,P.Andreasen,M.Huang

Key ref:

L.Jiang et al. (2015). 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. PubMed id: 25744057 DOI: 10.1016/j.biocel.2015.02.016

Date:

24-Nov-14 Release date: 21-Oct-15

Protein chain

P00749  (UROK_HUMAN) -  Urokinase-type plasminogen activator from Homo sapiens

Seq: 431 a.a.

Struc: 247 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.73 - u-plasminogen activator.
• Reaction: Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.

DOI no: 10.1016/j.biocel.2015.02.016

Int J Biochem Cell Biol 62:88-92 (2015)

PubMed id: 25744057

Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues.

L.Jiang, B.Zhao, P.Xu, H.P.Sørensen, J.K.Jensen, A.Christensen, M.Hosseini, N.C.Nielsen, K.J.Jensen, P.A.Andreasen, M.Huang.

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.