PDBsum entry 4x8t

Hydrolase/hydrolase inhibitor

PDB id: 4x8t

Contents

Protein chains

250 a.a.

55 a.a.

Ligands

3Z8

SO4 ×3

GOL

Metals

_CA

Waters ×143

PDB id:

4x8t

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor viia in complex with the inhibitor 7-chloro-3,4- dihydroisoquinolin-1(2h)-one

Structure:

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

2.20Å R-factor: 0.200 R-free: 0.221

Authors:

A.Wei

Key ref:

D.L.Cheney et al. (2015). Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening. J Med Chem, 58, 2799-2808. PubMed id: 25764119 DOI: 10.1021/jm501982k

Date:

10-Dec-14 Release date: 25-Mar-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/jm501982k

J Med Chem 58:2799-2808 (2015)

PubMed id: 25764119

Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening.

D.L.Cheney, J.M.Bozarth, W.J.Metzler, P.E.Morin, L.Mueller, J.A.Newitt, A.H.Nirschl, A.R.Rendina, J.K.Tamura, A.Wei, X.Wen, N.R.Wurtz, D.A.Seiffert, R.R.Wexler, E.S.Priestley.

ABSTRACT

A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.