title: Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4.
abstract: The crystal structure of human factor VIIa/soluble tissue factor (FVIIa/sTF) in complex with a highly selective peptide-mimetic FVIIa inhibitor which shows 1670-fold selectivity against thrombin inhibition has been solved at 2.6 A resolution. The inhibitor is bound to FVIIa/sTF at the S1, S2 and S3 sites and at the additional S1 subsite. Two charged groups, the amidino group in P2 and the carboxylate group in P4, form ionic interactions with Asp60 and Lys192 of FVIIa, respectively. Structural comparisons between factor VIIa and thrombin show that thrombin has oppositely charged residues, Lys60F and Glu192, in the S2 site and the S1 subsites, respectively. These data suggest that the utilization of the differences of charge distribution in the S2 site and the S1 subsites between FVIIa and thrombin is critical for achieving high selectivity against thrombin inhibition. These results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kadonosuj@chugai-pharm.co.jp
authors.forename: Shojiro
authors.initials: S
authors.lastname: Kadono
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Oh-Eda
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yabuta
authors.forename: Takaki
authors.initials: T
authors.lastname: Koga
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haramura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ono
authors.forename: Toru
authors.initials: T
authors.lastname: Esaki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Susumu
authors.initials: S
authors.lastname: Itoh
authors.forename: Masateru
authors.initials: M
authors.lastname: Ohta
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kozono
mesh_terms: D000925:Anticoagulants / Q000737:chemistry*; D000991:Antithrombins / Q000737:chemistry; D001777:Blood Coagulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D013925:Thromboplastin / Q000737:chemistry*
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D046911:Macromolecular Substances; D010455:Peptides; D013925:Thromboplastin; D015942:Factor VIIa