PDBsum entry 1ypm

Blood clotting/hydrolase inhibitor

PDB id: 1ypm

Contents

Protein chains

27 a.a.

250 a.a. *

Ligands

ASP-PHE-GLU-GLU-ILE-PRO-GLU-GLU-TYS-LEU

RA4

Waters ×155

* Residue conservation analysis

PDB id:

1ypm

Name:

Blood clotting/hydrolase inhibitor

Title:

X-ray crystal structure of thrombin inhibited by synthetic cyanopeptide analogue ra-1014

Structure:

Thrombin light chain. Chain: l. Synonym: coagulation factor ii. Thrombin heavy chain. Chain: h. Synonym: coagulation factor ii. Hirudin. Chain: i. Fragment: residues 1-10.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Synthetic: yes. Hirudo medicinalis. Organism_taxid: 6421. Other_details: chemically synthesized

Biol. unit:

Trimer (from PQS)

Resolution:

1.85Å R-factor: 0.191 R-free: 0.260

Authors:

J.Fokkens,G.Radau

Key ref:

G.Radau and J.Fokkens (2007). Design and X-ray crystal structures of human thrombin with synthetic cyanopeptide-analogues. Pharmazie, 62, 83-88. PubMed id: 17341023

Date:

31-Jan-05 Release date: 17-Jan-06

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 27 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 250 a.a.

Enzyme reactions

• Enzyme class: Chains L, H: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

Pharmazie 62:83-88 (2007)

PubMed id: 17341023

Design and X-ray crystal structures of human thrombin with synthetic cyanopeptide-analogues.

G.Radau, J.Fokkens.

ABSTRACT

Based on the X-ray crystals of cocrystallized cyanopeptide-trypsin and cyanopeptide-thrombin-com-plexes, a rational drug design succeeded in the establishment of suitable lead structures for the development of new potential inhibitors of thrombin. This report deals with the design and X-ray crystallography data of new synthetic, low-molecular weight cyanopeptide-analogues, RA-1008 and RA-1014, complexed with human alpha-thrombin at 1.85 A resolution. The crystal structures of the complexes reveal, by analogy with modeling studies, that the salt bridge of Asp189 to this type of synthetic thrombin inhibitors leads to an almost identically binding into the S1 specificity pocket in comparison to the complex of the natural products, whereas in the overall binding modes the P2-P4 substructures differ from those of the leads. The strongest member of the second series of described thrombin inhibitors, RA-1014, shows in the crystal complex with thrombin a slightly higher affinity towards the enzyme than RA-1008 as confirmed by inhibition tests. This result and other key informations will be helpful to design a more potent series of inhibitors.