PDBsum entry 6a8g

Hydrolase inhibitor/hydrolase

PDB id: 6a8g

Contents

Protein chains

12 a.a.

245 a.a.

Ligands

PO4 ×5

Waters ×34

PDB id:

6a8g

Name:

Hydrolase inhibitor/hydrolase

Title:

The crystal structure of mupain-1-ig in complex with mupa-spd at ph8.5

Structure:

Mupain-1-ig. Chain: p, e. Engineered: yes. Urokinase-type plasminogen activator chain b. Chain: a, b. Synonym: upa, mupa-spd. Engineered: yes. Mutation: yes

Source:

Synthetic: yes. Phage display vector ptdisp. Organism_taxid: 279974. Mus musculus. Mouse. Organism_taxid: 10090. Gene: plau. Expressed in: escherichia coli 'bl21-gold(de3)plyss ag'. Expression_system_taxid: 866768

Resolution:

2.53Å R-factor: 0.193 R-free: 0.246

Authors:

D.Wang,Y.S.Yang,L.G.Jiang,M.D.Huang,J.Y.Li,P.A.Andreasen,P.Xu,Z.Chen

Key ref:

D.Wang et al. (2019). Suppression of Tumor Growth and Metastases by Targeted Intervention in Urokinase Activity with Cyclic Peptides. J Med Chem, 62, 2172-2183. PubMed id: 30707839 DOI: 10.1021/acs.jmedchem.8b01908

Date:

08-Jul-18 Release date: 20-Feb-19

Protein chains

No UniProt id for this chain

Struc: 11 a.a.

Protein chains

P06869  (UROK_MOUSE) -  Urokinase-type plasminogen activator from Mus musculus

Seq: 433 a.a.

Struc: 245 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

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

DOI no: 10.1021/acs.jmedchem.8b01908

J Med Chem 62:2172-2183 (2019)

PubMed id: 30707839

Suppression of Tumor Growth and Metastases by Targeted Intervention in Urokinase Activity with Cyclic Peptides.

D.Wang, Y.Yang, L.Jiang, Y.Wang, J.Li, P.A.Andreasen, Z.Chen, M.Huang, P.Xu.

ABSTRACT

Urokinase-type plasminogen activator (uPA) is a diagnostic marker for breast and prostate cancers recommended by American Society for Clinical Oncology and German Breast Cancer Society. Inhibition of uPA was proposed as an efficient strategy for cancer treatments. In this study, we report peptide-based uPA inhibitors with high potency and specificity comparable to monoclonal antibodies. We revealed the binding and inhibitory mechanisms by combining crystallography, molecular dynamic simulation, and other biophysical and biochemical approaches. Besides, we showed that our peptides efficiently inhibited the invasion of cancer cells via intervening with the processes of the degradation of extracellular matrices. Furthermore, our peptides significantly suppressed the tumor growth and the cancer metastases in tumor-bearing mice. This study demonstrates that these uPA peptides are highly potent anticancer agents and reveals the mechanistic insights of these uPA inhibitors, which can be useful for developing other serine protease inhibitors.