Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
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Edited by Richard Wolfenden, University of North Carolina, Chapel Hill, NC, and approved September 11, 2009 (received for review March 11, 2009)
Abstract
Design of catalysts featuring multiple functional groups is a desirable, yet formidable goal. Antibody 13G5, which accelerates the cleavage of unactivated benzisoxazoles, is one of few artificial enzymes that harness an acid and a base to achieve efficient proton transfer. X-ray structures of the Fab-hapten complexes of wild-type 13G5 and active-site variants now afford detailed insights into its mechanism. The parent antibody preorganizes AspH35 and GluL34 to abstract a proton from substrate and to orient a water molecule for leaving group stabilization, respectively. Remodeling the environment of the hydrogen bond donor with a compensatory network of ordered waters, as seen in the GluL34 to alanine mutant, leads to an impressive 109-fold rate acceleration over the nonenzymatic reaction with acetate, illustrating the utility of buried water molecules in bifunctional catalysis. Generalization of these design principles may aid in creation of catalysts for other important chemical transformations.
Footnotes
- 3To whom correspondence may be addressed. hilvert{at}org.chem.ethz.ch or wilson{at}scripps.edu
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Author contributions: E.W.D., R.M., D.H., and I.A.W. designed research; E.W.D. and R.M. performed research; E.W.D. and R.M. contributed new reagents/analytic tools; E.W.D., R.M., D.H., and I.A.W. analyzed data; and E.W.D., R.M., D.H., and I.A.W. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 3FO0 (hapten complex of the 13G5 wild-type), 3FO1 (hapten complex of the 113G5-GluL34Ala variant), and 3FO2 (hapten complex of the 13G5-GluL34Gln variant)].
An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket
Article Classifications
- Biological Sciences
- Biochemistry
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