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.
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.
Kadono
Shojiro
S
Fuji Gotemba Research Laboratories, 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
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
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*
D000925:Anticoagulants; D000991:Antithrombins; D046911:Macromolecular Substances; D010455:Peptides; D013925:Thromboplastin; D015942:Factor VIIa