PDBsum entry 4zxy

Hydrolase/hydrolase inhibitor

PDB id: 4zxy

Contents

Protein chains

250 a.a.

55 a.a.

Ligands

4T1

SO4 ×3

GOL

Metals

_CA

Waters ×196

PDB id:

4zxy

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor viia in complex with the inhibitor (2r)-2-[(1-aminoisoquinolin- 6-yl)amino]-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7, 9,16,19-hexaene-3,12-dione

Structure:

Coagulation factor viia heavy chain. Chain: h. Fragment: unp residues 213-466. Synonym: proconvertin,serum prothrombin conversion accelerator,spca. Engineered: yes. Coagulation factor viia light chain. Chain: l. Fragment: unp residues 150-204. Synonym: proconvertin,serum prothrombin conversion accelerator,spca.

Source:

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

Resolution:

2.06Å R-factor: 0.192 R-free: 0.211

Authors:

A.Wei

Key ref:

E.S.Priestley et al. (2015). Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors. J Med Chem, 58, 6225-6236. PubMed id: 26151189 DOI: 10.1021/acs.jmedchem.5b00788

Date:

20-May-15 Release date: 22-Jul-15

Protein chain

P08709  (FA7_HUMAN) -  Coagulation factor VII from Homo sapiens

Seq: 466 a.a.

Struc: 250 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: 10.1021/acs.jmedchem.5b00788

J Med Chem 58:6225-6236 (2015)

PubMed id: 26151189

Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors.

E.S.Priestley, D.L.Cheney, I.DeLucca, A.Wei, J.M.Luettgen, A.R.Rendina, P.C.Wong, R.R.Wexler.

ABSTRACT

On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1' alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC2x = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.