Novel interactions of large P3 moiety and small P4 moiety in the binding of the peptide mimetic factor VIIa inhibitor.
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.
Kadono
Shojiro
S
Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kadonosuj@chugai-pharm.co.jp
Sakamoto
Akihisa
A
Kikuchi
Yasufumi
Y
Oh-Eda
Masayoshi
M
Yabuta
Naohiro
N
Yoshihashi
Kazutaka
K
Kitazawa
Takehisa
T
Suzuki
Tsukasa
T
Koga
Takaki
T
Hattori
Kunihiro
K
Shiraishi
Takuya
T
Haramura
Masayuki
M
Kodama
Hirofumi
H
Ono
Yoshiyuki
Y
Esaki
Toru
T
Sato
Haruhiko
H
Watanabe
Yoshiaki
Y
Itoh
Susumu
S
Ohta
Masateru
M
Kozono
Toshiro
T
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*
D019774:Blood Coagulation Factor Inhibitors; D010455:Peptides; D015942:Factor VIIa; D013917:Thrombin