title: High-resolution crystal structures of factor XIa coagulation factor in complex with nonbasic high-affinity synthetic inhibitors.
abstract: Factor XI (FXI) is a key enzyme in the coagulation pathway and an attractive target for the development of anticoagulant drugs. A small number of high-resolution crystal structures of FXIa in complex with small synthetic inhibitors have been published to date. All of these ligands have a basic P1 group and bind exclusively in the nonprime side of the active site of FXIa. Here, two structures of FXIa in complex with nonbasic inhibitors that occupy both the prime and nonprime sides of the active site are presented. These new structures could be valuable in the design and optimization of new FXIa synthethic inhibitors.
authors.affiliation: Merck Research Laboratories, MSD, Newhouse, Lanarkshire ML1 5SH, Scotland. xavier.fradera@merck.com
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: Bert
authors.initials: B
authors.lastname: Kazemier
authors.forename: Emma
authors.initials: E
authors.lastname: Carswell
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Arthur
authors.initials: A
authors.lastname: Oubrie
authors.forename: William
authors.initials: W
authors.lastname: Hamilton
authors.forename: Maureen
authors.initials: M
authors.lastname: Dempster
authors.forename: Stephan
authors.initials: S
authors.lastname: Krapp
authors.forename: Susanna
authors.initials: S
authors.lastname: Nagel
authors.forename: Anja
authors.initials: A
authors.lastname: Jestel
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015945:Factor XIa / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D040681:Structural Homology, Protein
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D015945:Factor XIa