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306X
mutation studies show that the interaction between protein cofactor tissue factor and methionine-306 in the serine protease domain of FVIIa triggers the activation process and suggested some ensuing steps on the pathway to the active conformation
A294V
-
mutant enzyme shows delayed activation by activated factor X as well as reduced activity towards peptidyl and macromolecular substrates without impairing the catalytic efficiency of the triad
C164V/V299C-FVIIa
-
introduction of a new disulfide bridge between Cys-159 and an introduced Cys at position 299
D102Q
-
inactive mutant enzyme
D186A
-
turnover-number for activation of factor X is 5.5fold lower than that of the wild-type factor VII, Km-value for activation of factor X is 1.2fold lower than that of the wild-type factor VII
D343H
-
mutant enzyme shows no activity with methanesulfonyl-D-cyclohexylalanyl-butyl-arginine p-nitroanilide, factor X and factor IX
D72N
-
the mutant shows 13% of wild type FVIIa signaling activity towards protease-activated receptor 2
DELTA360-329
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lower affinity for soluble tissue factor as compared to wild-type factor VIIa, 7fold smaller tissue factor-mediated acceleration of amidolytic activity compared to wild type factor VIIa
E154A
-
slightly increased Km-value and decreased turnover number compared to the wild-type enzyme
E154R
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
E296R
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
F256A
-
turnover-number and Km-value for activation of factor X are nearly identical to that of the wild-type factor VII
F374P
-
the specific clotting activity in presence of tissue factor is 50% of that of the wild-type factor VIIa
G372A
mutant G372A, both in the free and tissue factor-bound form, exhibit reduced cleavage of factor X and of D-Ile-Pro-Arg-4-nitroanilide (kcat increased compared to wild-type), and have increased Km values compared with wild-type FVIIa. Inhibition of mutant G372A +soluble tissue factor by 4-aminobenzamidine is characterized by a seven-fold higher Ki than obtained with wild-type. Crystallographic and modelling data suggest that the most active conformation of FVIIa depends on the backbone hydrogen bond between Gly372 and Arg315 in the 170 loop. Native and active site-inhibited mutant G372A binds soluble tissue factor with the same affinity as the corresponding forms of FVIIa
H101A
-
turnover-number for activation of factor X is 1.12fold lower than that of the wild-type factor VII, Km-value for activation of factor X is 1.23fold lower than that of the wild-type factor VII. Activation by factor Xa is significantly more slowly than that of wild-type enzyme. Tissue factor affinity and small substrate activity is similar to wild-type enzyme
H216A
-
mutant enzyme with decreased sensitivity to Zn2+ inhibition
H257A
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mutant enzyme with decreased sensitivity to Zn2+ inhibition
K192E
-
completely ineffective mutant enzyme
K305V
-
the ratio of turnover number to Km-value is 5.3fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
K341Q
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
L144A/R147A/D186A
-
turnover-number for activation of factor X is 239fold lower than that of the wild-type factor VII, Km-value for activation of factor X is 1.2fold higher than that of the wild-type factor VII
L280I/V299M-FVIIa
-
without description
L305V
-
mutant enzyme exhibits an increased rate of inhibition as compared with wild-type enzyme, both by D-Phe-Phe-Arg-chloromethyl ketone and antithombin III in presence of heparin. In complex with tissue factor both the amydolytic activity and the proteolytic activity are similar to that of the wild-type activity.The specific clotting activity in presence of tissue factor is 93% of that of the wild-type factor VIIa
L305V/K337A
-
the ratio of turnover number to Km-value is 6.3fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
L305V/M306D/D309S
-
amidylatic and proteolytic activity are virtually unaffected by the presence of tissue factor, 1.1fold increase. The specific clotting activity in presence of tissue factor is about 1% of that of the wild-type factor VIIa
M156K
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
M298K
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
M306N
-
amidolytic activity of the mutant enzyme is stimulated 7fold
M306N/N309S
-
amidolytic activity of the mutant enzyme is stimulated 1.5fold
M306S
-
amidolytic activity of the mutant enzyme is stimulated 9fold
M306T
-
amidolytic activity of the mutant enzyme is stimulated 12fold
N100A
-
turnover-number for activation of factor X is 3fold lower than that of the wild-type factor VII, Km-value for activation of factor X is 1.4fold lower than that of the wild-type factor VII
N100A/H101A/Y179A/F256A
-
turnover-number for activation of factor X is 3fold lower than that of the wild-type factor VII, Km-value for activation of factor X is nearly identical to that of the wild-type factor VII. Activation by factor Xa is significantly more slowly than that of wild-type enzyme
P10Q
-
site-directed mutagenesis, the mutant shows 2fold enhancement in membrane binding affinity over wild-type FVIIa
P10Q/K32E
-
site-directed mutagenesis, the mutant shows 27fold enhancement in membrane binding affinity over wild-type FVIIa, the double mutant displays a significantly improved procoagulant effect in haemophilic blood
P10Q/K32E/D33F/A34E
-
site-directed mutagenesis, the mutant shows 150-300fold enhancement in membrane binding affinity over wild-type FVIIa
P10Q/Q32E
-
mutant enzyme with elevated affinity for membrane. Phospholipid and cell-based assays show that mutant enzyme has an up to 40fold higher function then wild-type enzyme in both tissue-factor dependent reaction and in tissue factor independent reaction
Q143N
-
the mutant reduces interleukin-8 expression to background levels but maintains essentially normal pro-coagulant activity
Q143R
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
Q176G
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
Q217E
-
the mutant shows enhanced protease-activated receptor 2 activation
Q286R
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
Q40A
-
the mutant reduces interleukin-8 expression to background levels but maintains essentially normal pro-coagulant activity
Q40G
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
R147A
-
turnover-number for activation of factor X is 3.7fold lower than that of the wild-type factor VII, Km-value for activation of factor X is 1.2fold lower than that of the wild-type factor VII
R152Q
-
mutant enzyme shows no activity with methanesulfonyl-D-cyclohexylalanyl-butyl-arginine p-nitroanilide, factor X and factor IX
R353Q
in an observational study of 93 Japanese women 10 SNPs in relation to thrombosis or atherosclerosis are studied. Factor VII Arg353Gln and higher HDL-cholesterol (HDL-C) are linked to Arg/Arg carriers at higher levels
S344A
-
mutant enzyme shows no activity with methanesulfonyl-D-cyclohexylalanyl-butyl-arginine p-nitroanilide, factor X and factor IX
T151A
-
the mutant shows 13% of wild type FVIIa signaling activity towards protease-activated receptor 2
T151Q
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
T151S
-
the variant activates macromolecular coagulation substrates and supports signaling of the ternary tissue factor-FVIIa-Xa complex normally but is severely impaired in binary tissue factor-FVIIa-protease-activated receptor 2 signaling
T239A
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
T239G
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
T239I
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
T239Y
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
T293Q
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
T99A
-
the mutant shows 17% of wild type FVIIa signaling activity towards protease-activated receptor 2
T99Y
-
the mutation leads to enhanced protease-activated receptor 2 activation (2-3fold above the wild type FVIIa activity)
V154A
-
mutant enzyme shows reduced proteolytic activity towards factor X and undetectable activity towards factor IX
V154G
-
naturally occuring mutation, mutant enzyme with a zymogen-like form, markedly reduced activity towards peptidyl substrate and undetectable activity towards macromolecular substrates
V158D/D296V/M298Q
-
the ratio of turnover number to Km-value is 37.5fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
V158D/D296V/M298Q/K337A
-
the ratio of turnover number to Km-value is 56.3fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
V158D/D296V/M298Q/L305V
-
the ratio of turnover number to Km-value is 50fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
V158D/D296V/M298Q/L305V/L337
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the ratio of turnover number to Km-value is 100fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
V158D/E296V/M298Q
-
site-directed mutagenesis, FVIIa analogues with a stabilized activation domain and N-terminal insertion, the mutant shows increased activity compared to the wild-type enzyme
V158E
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
V21E
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
V21N/E154I/M156Q
-
mutant enzyme with stabilized amino-terminal Ile16-Asp194 salt bridge and enhanced catalytic function
V299M-FVIIa
-
modification of the first Leu-X-Val motif by the introduction of Met in the third position
Y179A
-
turnover-number for activation of factor X is nearly identical to that of the wild-type factor VII, Km-value for activation of factor X is 1.6fold lower than that of the wild-type factor VII. Activation by factor Xa is significantly more slowly than that of wild-type enzyme. Tissue factor affinity and small substrate activity is similar to wild-type enzyme
K192Q
-
mutant has 44% of the activity compared to the wild-type enzyme
K192Q
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
K337A
-
the ratio of turnover number to Km-value is 4.4fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
K337A
-
site-directed mutagenesis, the mutant shows increased activity compared to the wild-type enzyme
L144A
-
slightly increased Km-value and decreased turnover number compared to the wild-type enzyme
L144A
-
turnover-number for activation of factor X is 40fold lower than that of the wild-type factor VII, Km-value for activation of factor X is 1.6fold lower than that of the wild-type factor VII
M156Q
-
mutation has no influence on the amidolytic and proteolytic activity of tissue factor bound enzyme, increased affinity for tissue factor
M156Q
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
M298Q
-
the ratio of turnover number to Km-value is 6.9fold higher than that of the wild-type enzyme with factor X as substrate, increased inhibition rate compared to wild-type enzyme with antithrobin in presence of heparin
M298Q
-
site-directed mutagenesis, activity and active site structure in comparison to the wild-type
M306D
-
mutation abolishes the allosteric linkage between the active site and the binding interface with tissue factor. 2fold increase in amidolytic activity. In sharp contrast to the wild-type enzyme its binding kinetic to soluble tissue factor are unaltered after inactivation with D-Phe-Phe-Arg chloromethyl ketone
M306D
-
the mutant displays barely any tissue factor-induced enhancement in amidolytic activity or active site inhibitor affinity, no increased burial of the protease domain N-terminus and only partial protection of Asn-322 from deglycosylation
additional information
-
mutant enzyme which has all of the residues of the loop formed by a disulfide bond between Cys310 and Cys329 replaced with those of trypsin has lower affinity for soluble tissue factor as compared to wild-type enzyme, 2fold smaller tissue factor-mediated acceleration of amidolytic activity compared to wild type enzyme, the catalytic efficiencies of the mutant towards various chromogenic substrates are 2-18fold greater than those of the wild-type factor VIIa. As well as the wild-type enzyme the mutant exists predominantly in the zymogen-like state
additional information
-
construction of FVIIa analogues with a stabilized activation domain and N-terminal insertion
additional information
-
beside wild-type FVII, FVII-N145/322Q without N-glycosylation sites or FVII-S52/60A without O-glycosylation sites
additional information
-
changes in the protease domain in an analog of FVIIa with increased tissue factor-independent activity, NN1731, enhances platelet binding as well as proteolytic activity (50times)
additional information
-
deficiency of coagulation Factor VII results in spontaneous cardiac fibrosis in mice, resulting in diastolic and systolic cardiac dysfunction