PDBsum entry 4x6p

Hydrolase/hydrolase inhibitor

PDB id: 4x6p

Contents

Protein chains

236 a.a.

Ligands

NAG ×2

3YU ×2

CIT

GOL ×6

Waters ×306

PDB id:

4x6p

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia (pichia pastoris; c500s [c122s]) in complex with the inhibitor (2e)-n-{(1s)-1-[4-(3-amino-1h-indazol-6-yl)-1h-imidazol-2- yl]-2-phenylethyl}-3-[5-chloro-2-(1h-tetrazol-1-yl)phenyl]prop-2- enamide

Structure:

Coagulation factor xi, light chain. Chain: a, b. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: komagataella pastoris. Expression_system_taxid: 4922.

Resolution:

1.93Å R-factor: 0.166 R-free: 0.197

Authors:

S.Sheriff

Key ref:

D.J.Pinto et al. (2015). Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. Bioorg Med Chem Lett, 25, 1635-1642. PubMed id: 25728130 DOI: 10.1016/j.bmcl.2015.01.028

Date:

08-Dec-14 Release date: 18-Feb-15

Protein chains

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 236 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.4.21.27 - coagulation factor XIa.
• Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.

DOI no: 10.1016/j.bmcl.2015.01.028

Bioorg Med Chem Lett 25:1635-1642 (2015)

PubMed id: 25728130

Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.

D.J.Pinto, J.M.Smallheer, J.R.Corte, E.J.Austin, C.Wang, T.Fang, L.M.Smith, K.A.Rossi, A.R.Rendina, J.M.Bozarth, G.Zhang, A.Wei, V.Ramamurthy, S.Sheriff, J.E.Myers, P.E.Morin, J.M.Luettgen, D.A.Seiffert, M.L.Quan, R.R.Wexler.

ABSTRACT

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7nM and modest oral exposure in dogs.