PDBsum entry 3lc5

Hydrolase/hydrolase inhibitor

PDB id: 3lc5

Contents

Protein chains

235 a.a. *

54 a.a. *

Ligands

IZX

Metals

_CA

Waters ×13

* Residue conservation analysis

PDB id:

3lc5

Name:

Hydrolase/hydrolase inhibitor

Title:

Selective benzothiophine inhibitors of factor ixa

Structure:

Coagulation factor ix. Chain: a. 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.

Source:

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

Resolution:

2.62Å R-factor: 0.213 R-free: 0.277

Authors:

S.Wang,R.Beck

Key ref:

S.Wang et al. (2010). Structure based drug design: development of potent and selective factor IXa (FIXa) inhibitors. J Med Chem, 53, 1473-1482. PubMed id: 20121197

Date:

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

Protein chain

P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens

Seq: 461 a.a.

Struc: 235 a.a.

Protein chain

P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens

Seq: 461 a.a.

Struc: 54 a.a.*

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

Enzyme reactions

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

J Med Chem 53:1473-1482 (2010)

PubMed id: 20121197

Structure based drug design: development of potent and selective factor IXa (FIXa) inhibitors.

S.Wang, R.Beck, A.Burd, T.Blench, F.Marlin, T.Ayele, S.Buxton, C.Dagostin, M.Malic, R.Joshi, J.Barry, M.Sajad, C.Cheung, S.Shaikh, S.Chahwala, C.Chander, C.Baumgartner, H.P.Holthoff, E.Murray, M.Blackney, A.Giddings.

ABSTRACT

On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.