PDBsum entry 5wb6

Hydrolase/hydrolase inhibitor

PDB id: 5wb6

Contents

Protein chain

238 a.a.

Ligands

9ZM

SO4

EDO ×14

Waters ×142

PDB id:

5wb6

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor methyl [(11s)-11-({(2e)-3-[5- chloro-2-(1h-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-6-fluoro-2-oxo- 1,3,4,10,11,13-hexahydro-2h-5,9:15,12-di(azeno)-1,13- benzodiazacycloheptadecin-18-yl]carbamate

Structure:

Coagulation factor xi. Chain: a. Fragment: light chain (unp residues 388-625). Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.35Å R-factor: 0.201 R-free: 0.236

Authors:

S.Sheriff

Key ref:

C.Wang et al. (2017). Macrocyclic factor XIa inhibitors. Bioorg Med Chem Lett, 27, 4056-4060. PubMed id: 28780160 DOI: 10.1016/j.bmcl.2017.07.048

Date:

28-Jun-17 Release date: 02-Aug-17

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 238 a.a.*

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

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.2017.07.048

Bioorg Med Chem Lett 27:4056-4060 (2017)

PubMed id: 28780160

Macrocyclic factor XIa inhibitors.

C.Wang, J.R.Corte, K.A.Rossi, J.M.Bozarth, Y.Wu, S.Sheriff, J.E.Myers, J.M.Luettgen, D.A.Seiffert, R.R.Wexler, M.L.Quan.

ABSTRACT

A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.