PDBsum entry 4jzf

Hydrolase/hydrolase inhibitor

PDB id: 4jzf

Contents

Protein chains

254 a.a.

55 a.a.

Ligands

1NL

SO4 ×4

GOL ×3

Metals

_CA

Waters ×365

PDB id:

4jzf

Name:

Hydrolase/hydrolase inhibitor

Title:

Structure of factor viia in complex with the inhibitor 2-{2-[(3- carbamoylphenyl)carbamoyl]-6-methoxypyridin-3-yl}-5-{[(2s)-1-hydroxy- 3,3-dimethylbutan-2-yl]carbamoyl}benzoic acid

Structure:

Factor viia (heavy chain). Chain: h. Fragment: unp residues 213-466. Synonym: factor vii heavy chain, activated factor viia heavy chain, coagulation factor vii, proconvertin, serum prothrombin conversion accelerator, spca. Engineered: yes. Factor viia (light chain). Chain: l.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f7. Expressed in: cricetinae. Expression_system_taxid: 10026. Expression_system_taxid: 10026

Resolution:

1.84Å R-factor: 0.181 R-free: 0.199

Authors:

A.Wei,R.Anumula

Key ref:

S.A.Bolton et al. (2013). Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold. Bioorg Med Chem Lett, 23, 5239-5243. PubMed id: 23927973 DOI: 10.1016/j.bmcl.2013.06.028

Date:

02-Apr-13 Release date: 21-Aug-13

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 254 a.a.

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 55 a.a.

Enzyme reactions

• Enzyme class: Chains H, L: E.C.3.4.21.21 - coagulation factor VIIa.
• Reaction: Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

DOI no: 10.1016/j.bmcl.2013.06.028

Bioorg Med Chem Lett 23:5239-5243 (2013)

PubMed id: 23927973

Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold.

S.A.Bolton, J.C.Sutton, R.Anumula, G.S.Bisacchi, B.Jacobson, W.A.Slusarchyk, U.D.Treuner, S.C.Wu, G.Zhao, Z.Pi, S.Sheriff, R.A.Smirk, S.Bisaha, D.L.Cheney, A.Wei, W.A.Schumacher, K.S.Hartl, E.Liu, R.Zahler, S.M.Seiler.

ABSTRACT

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.