title: Crystal structure of human factor VIIa/tissue factor in complex with peptide mimetic inhibitor.
abstract: The 3D structure of human factor VIIa/soluble tissue factor in complex with a peptide mimetic inhibitor, propylsulfonamide-D-Thr-Met-p-aminobenzamidine, is determined by X-ray crystallography. As compared with the interactions between thrombin and thrombin inhibitors, the interactions at S2 and S3 sites characteristic of factor VIIa and factor VIIa inhibitors are revealed. The S2 site has a small pocket, which is filled by the hydrophobic methionine side chain in P2. The small S3 site fits the small size residue, D-threonine in P3. The structural data and SAR data of the peptide mimetic inhibitor show that these interactions in the S2 and S3 sites play an important role for the improvement of selectivity versus thrombin. The results will provide valuable information for the structure-based drug design of specific inhibitors 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: 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: 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*; D001550:Benzamidines / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D015942:Factor VIIa / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D013917:Thrombin / Q000737:chemistry; D013925:Thromboplastin / Q000737:chemistry*
chemical_list: D000925:Anticoagulants; D001550:Benzamidines; D004151:Dipeptides; D010455:Peptides; C495967:propylsulfonamide-threonyl-methionyl-4-aminobenzamidine; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin