PDBsum entry 3lc3

Hydrolase/hydrolase inhibitor

PDB id: 3lc3

Contents

Protein chains

235 a.a. *

57 a.a. *

Ligands

IYX ×4

Metals

_CA ×2

Waters ×420

* Residue conservation analysis

PDB id:

3lc3

Name:

Hydrolase/hydrolase inhibitor

Title:

Benzothiophene inhibitors of factor ixa

Structure:

Coagulation factor ix. Chain: a, c. Fragment: residues 227-461. Synonym: christmas factor, plasma thromboplastin component, ptc, coagulation factor ixa light chain, coagulation factor ixa heavy chain. Engineered: yes. Coagulation factor ix. Chain: b, d.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f9. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

1.90Å R-factor: 0.199 R-free: 0.260

Authors:

S.Wang,R.Beck

Key ref:

S.Wang et al. (2010). Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis. J Med Chem, 53, 1465-1472. PubMed id: 20121198

Date:

09-Jan-10 Release date: 23-Feb-10

Protein chains

P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens

Seq: 461 a.a.

Struc: 235 a.a.

Protein chains

P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens

Seq: 461 a.a.

Struc: 57 a.a.*

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

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.3.4.21.22 - coagulation factor IXa.
• Reaction: Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

J Med Chem 53:1465-1472 (2010)

PubMed id: 20121198

Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.

S.Wang, R.Beck, T.Blench, A.Burd, S.Buxton, M.Malic, T.Ayele, S.Shaikh, S.Chahwala, C.Chander, R.Holland, S.Merette, L.Zhao, M.Blackney, A.Watts.

ABSTRACT

FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.