Crystal structure of a catalytic antibody Fab with esterase-like activity.
BACKGROUND
Antibodies with catalytic properties can be prepared by eliciting an antibody response against 'transition state analog' haptens. The specificity, rate and number of reaction cycles observed with these antibodies more closely resemble the properties of enzymes than any of the many other known enzyme-mimicking systems.


RESULTS
We have determined to 3 A resolution the first X-ray structure of a catalytic antibody Fab. This antibody catalyzes the hydrolysis of a p-nitrophenyl ester. In conjunction with binding studies in solution, this structure of the uncomplexed site suggests a model for transition state fixation where two tyrosines mimic the oxyanion binding hole of serine proteases. A comparison with the structures of known Fabs specific for low molecular weight haptens reveals that this catalytic antibody has an unusually long groove at its combining site.


CONCLUSIONS
Since transition state analogs contain elements of the desired product, product inhibition is a severe problem in antibody catalysis. The observation of a long groove at the combining site may relate to the ability of this catalytic antibody to achieve multiple cycles of reaction.
Golinelli-Pimpaneau
B
B
Laboratoire de Biologie Structurale, UMR 9920 CNRS Université Paris Sud Bat 34, CNRS, Gif sur Yvette, France.
Gigant
B
B
Bizebard
T
T
Navaza
J
J
Saludjian
P
P
Zemel
R
R
Tawfik
D S
DS
Eshhar
Z
Z
Green
B S
BS
Knossow
M
M
D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray / Q000379:methods; D004950:Esterases / Q000737:chemistry / Q000378:metabolism*; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000378:metabolism*; D008968:Molecular Conformation; D009596:Nitrophenols / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013379:Substrate Specificity
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D009596:Nitrophenols; D004950:Esterases