PDBsum entry 4mnw

Hydrolase/hydrolase inhibitor

PDB id: 4mnw

Contents

Protein chains

245 a.a.

14 a.a.

Ligands

SO4 ×2

GOL ×5

ACT

ZBR

Waters ×169

PDB id:

4mnw

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of urokinase-type plasminogen activator (upa) complexed with bicyclic peptide uk749

Structure:

Urokinase-type plasminogen activator chain b. Chain: a. Fragment: catalytic domain (unp residues 179-423). Synonym: u-plasminogen activator, upa. Engineered: yes. Mutation: yes. Bicyclic peptide uk749. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: plau. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek 293. Synthetic: yes. Other_details: modified with 1,3,5-tris(bromomethyl)benzene (tbmb)

Resolution:

1.49Å R-factor: 0.156 R-free: 0.171

Authors:

S.Chen,F.Pojer,C.Heinis

Key ref:

S.Chen et al. (2014). Peptide ligands stabilized by small molecules. Angew Chem Int Ed Engl, 53, 1602-1606. PubMed id: 24453110 DOI: 10.1002/anie.201309459

Date:

11-Sep-13 Release date: 05-Feb-14

Protein chain

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

Seq: 431 a.a.

Struc: 245 a.a.*

Protein chain

No UniProt id for this chain

Struc: 14 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

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

DOI no: 10.1002/anie.201309459

Angew Chem Int Ed Engl 53:1602-1606 (2014)

PubMed id: 24453110

Peptide ligands stabilized by small molecules.

S.Chen, D.Bertoldo, A.Angelini, F.Pojer, C.Heinis.

ABSTRACT

Bicyclic peptides generated through directed evolution by using phage display offer an attractive ligand format for the development of therapeutics. Being nearly 100-fold smaller than antibodies, they promise advantages such as access to chemical synthesis, efficient diffusion into tissues, and needle-free application. However, unlike antibodies, they do not have a folded structure in solution and thus bind less well. We developed bicyclic peptides with hydrophilic chemical structures at their center to promote noncovalent intramolecular interactions, thereby stabilizing the peptide conformation. The sequences of the peptides isolated by phage display from large combinatorial libraries were strongly influenced by the type of small molecule used in the screen, thus suggesting that the peptides fold around the small molecules. X-ray structure analysis revealed that the small molecules indeed formed hydrogen bonds with the peptides. These noncovalent interactions stabilize the peptide-protein complexes and contribute to the high binding affinity.