title: Novel interactions of large P3 moiety and small P4 moiety in the binding of the peptide mimetic factor VIIa inhibitor.
abstract: Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is seen as a promising target for developing new anticoagulant drugs. A novel peptide mimetic factor VIIa inhibitor, ethylsulfonamide-d-biphenylalanine-Gln-p-aminobenzamidine, shows 100-fold selectivity against thrombin in spite of its large P3 moiety, unlike previously reported FVIIa/TF selective inhibitors. X-ray crystal structure analysis reveals that the large P3 moiety, d-biphenylalanine, and the small P4 moiety, ethylsulfonamide, make novel interactions with the 170-loop and Lys192 of FVIIa/TF, respectively, accompanying ligand-induced conformational changes of the 170-loop, Gln217, and Lys192. Structural comparisons of FVIIa with thrombin and amino acid sequence comparisons among coagulation serine proteases suggest that these interactions play an important role in achieving selective inhibition for FVIIa/TF.
authors.affiliation: Fuji Gotemba Research Labs, 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: Kazutaka
authors.initials: K
authors.lastname: Yoshihashi
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kitazawa
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
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: D000595:Amino Acid Sequence; D001665:Binding Sites; D032701:Biomimetics / Q000379:methods*; D019774:Blood Coagulation Factor Inhibitors / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D013917:Thrombin / Q000737:chemistry*
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D010455:Peptides; D015942:Factor VIIa; D013917:Thrombin