PDBsum entry 6c0s

Hydrolase/hydrolase inhibitor

PDB id: 6c0s

Contents

Protein chain

238 a.a.

Ligands

EEJ

SO4

EDO ×12

Waters ×141

PDB id:

6c0s

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor methyl (4-{6-[(1s)-2-[(3r)-1- acetylpiperidin-3-yl]-1-({(2e)-3-[5-chloro-2- (1h-tetrazol-1-yl) phenyl]prop-2-enoyl}amino)ethyl]-3-chloropyridazin-4-yl}phenyl) 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 bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.35Å R-factor: 0.197 R-free: 0.226

Authors:

S.Sheriff

Key ref:

Z.Hu et al. (2018). Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors. Bioorg Med Chem Lett, 28, 987-992. PubMed id: 29501396 DOI: 10.1016/j.bmcl.2018.02.049

Date:

02-Jan-18 Release date: 07-Mar-18

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.2018.02.049

Bioorg Med Chem Lett 28:987-992 (2018)

PubMed id: 29501396

Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors.

Z.Hu, C.Wang, W.Han, 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

Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.