PDBsum entry 6twc

Blood clotting

PDB id: 6twc

Contents

Protein chains

238 a.a.

12 a.a.

Ligands

GLU-CYS-THR-THR-LYS-ILE-LYS-PRO

ACN ×2

PDB id:

6twc

Name:

Blood clotting

Title:

Crystal structure of the catalytic domain of the coagulation factor xia in complex with double bridged peptide f21

Structure:

Coagulation factor xi. Chain: a. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Coagulation factor xi. Chain: h. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Double bridged peptide f21.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.86Å R-factor: 0.216 R-free: 0.259

Authors:

X.D.Kong,F.Pojer,C.Heinis

Key ref:

X.D.Kong et al. (2020). De novo development of proteolytically resistant therapeutic peptides for oral administration. Nat Biomed Eng, 4, 560-571. PubMed id: 32393891 DOI: 10.1038/s41551-020-0556-3

Date:

13-Jan-20 Release date: 20-May-20

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 238 a.a.*

Protein chain

No UniProt id for this chain

Struc: 12 a.a.

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

Enzyme reactions

• Enzyme class: Chain A: E.C.3.4.21.27 - coagulation factor XIa.
• Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.

DOI no: 10.1038/s41551-020-0556-3

Nat Biomed Eng 4:560-571 (2020)

PubMed id: 32393891

De novo development of proteolytically resistant therapeutic peptides for oral administration.

X.D.Kong, J.Moriya, V.Carle, F.Pojer, L.A.Abriata, K.Deyle, C.Heinis.

ABSTRACT

The oral administration of peptide drugs is hampered by their metabolic instability and limited intestinal uptake. Here, we describe a method for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases. By using phage display to screen large libraries of genetically encoded double-bridged peptides on protease-resistant fd bacteriophages, we generated a peptide inhibitor of the coagulation Factor XIa with nanomolar affinity that resisted gastrointestinal proteases in all regions of the gastrointestinal tract of mice after oral administration, enabling more than 30% of the peptide to remain intact, and small quantities of it to reach the blood circulation. We also developed a gastrointestinal-protease-resistant peptide antagonist for the interleukin-23 receptor, which has a role in the pathogenesis of Crohn's disease and ulcerative colitis. The de novo generation of targeted peptides that resist proteolytic degradation in the gastrointestinal tract should help the development of effective peptides for oral delivery.