PDBsum entry 4yzu

Hydrolase/hydrolase inhibitor

PDB id: 4yzu

Contents

Protein chains

235 a.a.

57 a.a.

Ligands

4K6

NHE

Metals

_CL

_NA

Waters ×335

PDB id:

4yzu

Name:

Hydrolase/hydrolase inhibitor

Title:

Rapid development of two factor ixa inhibitors from hit to lead

Structure:

Coagulation factor ix. Chain: a. Fragment: peptidase s1 domain (unp residue 227-461). Synonym: christmas factor,plasma thromboplastin component,ptc. Engineered: yes. Mutation: yes. Coagulation factor ix. Chain: b. Fragment: egf-like 2 domain (unp residues 131-191).

Source:

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

Resolution:

1.41Å R-factor: 0.146 R-free: 0.161

Authors:

A.Hruza,P.Reichert

Key ref:

D.L.Parker et al. (2015). Rapid development of two factor IXa inhibitors from hit to lead. Bioorg Med Chem Lett, 25, 2321-2325. PubMed id: 25937013 DOI: 10.1016/j.bmcl.2015.04.025

Date:

25-Mar-15 Release date: 20-May-15

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: 57 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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.

DOI no: 10.1016/j.bmcl.2015.04.025

Bioorg Med Chem Lett 25:2321-2325 (2015)

PubMed id: 25937013

Rapid development of two factor IXa inhibitors from hit to lead.

D.L.Parker, S.Walsh, B.Li, E.Kim, A.Sharipour, C.Smith, Y.H.Chen, R.Berger, B.Harper, T.Zhang, M.Park, M.Shu, J.Wu, J.Xu, S.Dewnani, E.C.Sherer, A.Hruza, P.Reichert, W.Geissler, L.Sonatore, K.Ellsworth, J.Balkovec, W.Greenlee, H.B.Wood.

ABSTRACT

Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9μM to 0.016μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2μM to 0.09μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.